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Scope of Drug Metabolism toward Xenobiotic Detoxification

Over the course of evolution organisms were exposed to environmental compounds of negligible nutritive value. These have variably been called 'foreign compounds' or 'xenobiotics.' Also the term 'drug' is used for them in contrast to the narrower term 'therapeutic drug' to specifically designate those xenobiotics that are intended for clinical use. Organisms that developed systems enabling them to get rid of these xenobiotics before they could accumulate to toxic levels had an evolutionary advantage. Such systems therefore had an obvious scope toward detoxification.1 A further need was the ability to detoxify 'future unknowns.' Therefore, the enzymes exclusively or predominantly catalyzing the metabolism of xenobiotics usually (1) have a very broad substrate specificity and (2) exist in large families or superfamilies of enzymes each one of them possessing a broad but distinct substrate specificity, which in part overlaps with the specificities of the other isoenzymes.1 The...

The Phase Concept of Drug Metabolism and Its Importance for Toxification versus Detoxification

The phase concept of drug metabolism is described elsewhere in this book (see 5.05 Principles of Drug Metabolism 1 Redox Reactions 5.06 Principles of Drug Metabolism 2 Hydrolysis and Conjugation Reactions). With respect to toxification versus detoxification it is important that depending on their chemical nature the functional groups introduced in the phase I of drug metabolism can be classified as electrophilic or nucleophilic (Figure 1). Functional groups with an electrophilic carbon are, for example, epoxides or a,b-unsaturated carbonyl groups. Nucleophilic substituents are, for example, hydroxyl, amino, sulfhydryl, or carboxylic groups. Owing to their ability to react with electron-rich substituents in important intracellular steering molecules such as proteins and nucleic acids, electrophilic metabolites can depending on their individual chemical reactivity - be highly cyto-toxic and or mutagenic. Nucleophilic metabolites, however, usually do not covalently modify endogenous...

Toxification versus Detoxification

The key point is that a given species was not able to 'predict' what kind of xenobiotics it would be exposed in future since the organisms and their constituents in its environment obviously also underwent evolutionary changes. Thus, excretory systems of low specificity and hence high flexibility provided an evolutionary advantage. However, there was a price to pay for this flexibility. The low substrate specificity of the enzymes catalyzing the reactions allowing for a vast array of 'unforeseen' lipophilic xenobiotics to ultimately be converted to metabolites sufficiently hydrophilic for excretion quite frequently led to toxic intermediary metabolites.1 Therefore, drug metabolism leads to both detoxification and toxification. Indeed, practically all drug-metabolizing enzymes that have been investigated so far play dual roles detoxification and toxification. However, for individual structural elements of a given drug it becomes increasingly possible to predict whether a given enzyme...

Antecedents to Cultivation Some Case Studies

In common with many hunter-gatherer people, Aborigine women played a key role in acquiring food for their group and were the main collectors of plant foods. As today, yams were found by identifying the leaves and then tracing the tendrils of each plant, entwined among the branches of nearby bushes, back to their source. A digging stick was then used to excavate the yams by following the tendrils underground until the main body of the plant was located. Great care was taken not to remove the whole plant when foraging, so that some was left behind to ensure vegetative regeneration. The bitter tasting Dioscorea bulbifera (bitter yam, air potato) was cooked in an earthen oven (Jones and Meeham 1989, 124). Snail shells with holes cut in them were then used to grate the tubers. The prepared material was afterwards left to soak overnight to detoxify it. Other yams, such as the long yam D. transversa, required less stringent preparation.

Endoplasmic reticulum

The endoplasmic reticulum comprises two morphologically distinct systems that are interconnected to form a single membrane system. The functions of the system broadly consist of synthesis, storage, transport and detoxification. The endoplasmic reticulum consists of membrane-enclosed branching tubules and flattened sacs (cisternae) and vesicles, which intercommunicate throughout the cytosol forming an intracellular transport network. The cisternal space is enclosed within. The endoplasmic reticulum is the largest subcellular organelle. Site of mixed function oxidase systems in the liver, which detoxify various organic compounds.

Agranular Smooth Endoplasmic Reticulum sER

Lo The morphological difference between smooth or agranular ER and the gra-3 nular form of ER is the absence of ribosomes. Rough ER proliferates to smooth ER, where the synthesis of lipid and steroid molecules occurs, cholesterol among others. In addition, sER metabolizes many xenobiotic substances, such as pharmaceuticals, pesticides and carcinogens, etc. The sER is therefore the most important intracellular detoxification system. It usually takes the form of a tightly woven network of branched tubules of various diameters (30-100nm). Cisternae are usually absent. As in liver cells, for example, rough and smooth ER are often confluent. There is a pronounced expansion of the agranular ER (sER) in steroid hormone-producing cells, particularly in cells of the adrenal cortex, the corpus luteum and in the interstitial cells of the testes. Smooth ER is called sarcoplasmic reticulum in striated skeletal muscle tissue, where it serves to store calcium.

The Genome of Dictyostelium discoideum Adam Kuspa and William F Loomis

The Dictyostelium discoideum genome has been sequenced, assembled and annotated to a high degree of reliability. The parts-list of proteins and RNA encoded by the six chromosomes can now be accessed and analyzed. One of the initial surprises was the remarkably large number of genes that are shared with plants, animals, and fungi that must have been present in their common progenitor over a billion years ago. The genome encodes a total of about 10,300 proteins including protein families involved in cytoskeletal control, posttranslational protein modification, detoxification, secondary metabolism, cell adhesion, and signal transduction. The genome has a higher proportion of homopolymeric tracts and simple sequence repeats, such as CAA than most other genomes. Triplet repeats in translated regions produce the highest known proportion of polyglutamine tracts in any known proteome. Phylogenetic analyses based on complete proteomes confirm that the amoebozoa are a sister group to the...

Pharmacological Interventions And Treatment Implications

Naltrexone is used to help patients avoid relapse after they have been detoxified from opioid dependence. Its main therapeutic action is to occupy mu opioid receptors in the brain with a 100-fold higher affinity than agonists such as methadone or heroin, so that addictive opioids cannot link up with them and stimulate the brain's reward system. Naltrexone does not activate the G-protein-coupled cyclic AMP system and does not increase or decrease levels of cyclic AMP inside the neuron, and it does not promote these brain processes that produce feelings of pleasure (Kosten & Kleber, 1984). An individual who is adequately dosed with naltrexone does not obtain any pleasure from addictive opioids and is less motivated to use them. An interesting neurobiological effect of naltrexone is that it appears to increase the number of available mu opiate receptors, which may help to renormalize the imbalance between the receptors and G-protein coupling to cyclic AMP (Kosten, 1990). Naltrexone is...

Trends In Treatment And Prevention

Detoxification became prevalent in the mid-1900s. Public detoxification facilities, established first in Eastern Europe, spread throughout the world. For many patients, this resource offers an entree into recovery. For others, revolving door detoxification may actually produce lifelong institutionalization on the installment plan (Gallant et al., 1973). The problem of the treatment-resistant public inebriate exists today in all parts of the United States. More sophisticated methods of pharmacotherapy have appeared recently, although these remain few in comparison with other areas of medicine. Safe detoxification is possible through increased basic and clinical appreciation of withdrawal syndromes. Disulfiram, naltrexone, buprenorphine, and methadone may be selectively prescribed as maintenance drugs in the early difficult months and years of recovery. Other medications are currently being investigated for use in special circumstances.

Conjugations with Glutathione 506371 Glutathione and glutathione transferases

Glutathione (64, Figure 22 GSH) is a thiol-containing tripeptide of major significance in the detoxification of drugs and other xenobiotics. In the body, it exists in a redox equilibrium between the reduced form (GSH) and an oxidized form (GSSG). The metabolism of glutathione (i.e., its synthesis, redox equilibrium, and degradation) is quite complex and involves a number of enzymes.112-115 Glutathione reacts in a variety of ways, one of which is its redox capacity. Indeed, GSH can reduce peroxides (a reaction catalyzed by glutathione peroxidase) and organic nitrates in its GSSG form, glutathione can oxidize the superoxide anion radical. Of major significance in detoxification reactions is the capacity of GSH (and other endogenous thiols including albumin) to scavenge free radicals, in particular radical oxygen species (e.g., R, HO, HOO, ROO). As such, glutathione and other thiols have a critical role to play in cellular protection.116 The reactions involved are highly complex and can...

Substrates of glutathione transferases

Quinones (ortho- and para-) and quinoneimines are structurally very similar to a,b-unsaturated carbonyls. They react with glutathione by two distinct and competitive routes, one of which is a reduction to the hydroquinone or aminophenol, where GSH does not react covalently with the substrate but emerges in the oxidized form (GSSG). The other route is relevant to the present context, being a nucleophilic addition to form a conjugate. The reaction has physiological significance since endogenous metabolites such as quinone metabolites of estrogens are conjugated to glutathione. A medicinal example is provided by the toxic quinoneimine metabolite (71, Figure 23 see 5.05 Principles of Drug Metabolism 1 Redox Reactions 5.08 Mechanisms of Toxification and Detoxification which Challenge Drug Candidates and Drugs) of paracetamol (30). Its glutathione conjugate (71) is not excreted as such in humans dosed with the drug, but as the mercapturic acid (67, Figure 22). The reaction is one of major...

Multiplicity and ligand specificity

Which are bioactivated byAOX (orXOR). AOXalso plays an important role in the detoxification of potentially reactive iminium ions that can be generated by P450 or MAO, often from cyclic tertiary amines, e.g., nicotine.40 Menadione, isovanillin, and raloxifene are useful diagnostic inhibitors of AOX.65

Biochemistry of extramitochondrial ubiquinone

The NADH-cytochrome b5 reductase has been found in the cytosolic side of all endomembranes and the plasma membrane, and in the erythrocyte cytosol.9,11,38,39 The reductase was known primarily by its function in the reduction of microsomal cytochrome b5 to transfer electrons to the nonheme iron fatty acid desaturase,40 and as a methemoglobin reductase.39 This enzyme has also been related to the detoxification based on cytochrome P450 as an alternative source of electrons.10 In addition, cytochrome b5 reductase reduces a variety of quinones by a one-electron mechanism to generate the corresponding semiquinones and hydroquinones in the absence of cytochrome b5,10 and has been proposed to be involved in CoQH2 regeneration in the plasma membrane.9,11,41 Incubation of pig liver plasma membranes with NADH results in the reduction of endogenous CoQ10 to CoQ10H2, an activity attributed to the NADH-cytochrome b5 reductase.42

Tissue distribution and ontogenic development

The ontogeny of SULTs was studied recently by Richard et al.11 in the developing liver, lung, and brain. SULT1A1 enzymatic activity was higher in fetal tissues than in postnatal liver. Also SULT1A3 was expressed at higher levels in early stages of development, decreased gradually in the late fetal early neonatal liver and was not observed in adult liver. In the lung, high SULT1A3 activity was observed in the fetus compared to neonatal levels. Therefore, the developing fetus clearly possesses significant sulfation capabilities. This could be a consequence of the important role sulfation plays in the homeostasis of hormones and other endogenous compounds that are important for development or because of the need for xenobiotic detoxification in the fetus where other conjugating enzymes, notably the UGTs, are not expressed at high levels until the neonatal stage.

The selection and analysis of transformants

The increasing knowledge of modes of action of herbicides, and rapid progress in molecular genetics have led to the identification, isolation and modification of numerous genes encoding the target proteins for herbicides. Engineering herbicide tolerance into crops has proved useful not only as a selection system, but also as a valuable trait for commercial agriculture. To be useful in agriculture, herbicides must distinguish between crop plant and weed. Although they are designed to affect significant processes in plants such as photosynthesis and amino-acid biosynthesis, these processes are common to both crops and weeds. Consequently, at present, selectivity is based on differential herbicide uptake between weed and crop, or controlled timing and site of application of the herbicide by the crop plant. As to the different strategies employed to introduce herbicide tolerance in crops, the overexpression or modification of the biochemical target of the herbicide52-4 and...

Sulfotransferases EC 282

Sulfotransferases (SULTs)55 catalyze the transfer of a sulfonyl group from 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to nucleophilic substituents of their substrates, analogous to the UGTs. Accordingly, SULTs are often detoxifying enzymes for the same reasons discussed above for the UGTs. On the other hand, sulfoconjugation is in a predictable fashion also an important toxification mechanism for several types of precarcinogens.55,56 Aromatic hydroxylamines, metabolically produced from aromatic amines by CYP, are metabolized by SULT to aromatic N-O-sulfate esters, which heterolytically decompose to the sulfate anion and to the genotoxic nitrenium ions. Sulfation of benzylic alcohols leads to the formation of reactive carbenium ions after cleaving off the sulfate group. Thus, mice with SULTs have a substrate spectrum similar to that of the UGTs, except they do not conjugate carboxylic acids. Generally, SULTs have a lower Km than UGTs. Hence, an important detoxification function of...

Acetyltransferases included in EC 231

Since, in contrast to most phase II reactions of drug metabolism, the metabolites of NAT reactions (typically amides) are usually less hydrophilic than their parent compounds (typically amines), the function of NAT appears to be primarily the inactivation of biologically active, potentially toxic compounds, rather than a conversion to more hydrophilic metabolites.1 The role of NATs in the detoxification of the procarcinogenic aryl amines is ambivalent but dependent on the nature of the substrate N-acetylation of the aromatic amine is a detoxification reaction, since it competes with the formation of the hydroxylamine, i.e., with the initiation of the toxification pathway. However, if N-oxidation takes place first, the resulting hydroxylamine is also a substrate for NAT leading to the N-O-acetate ester (an acetoxyamino-group) from which acetate is easily cleaved off, which results in the generation of a reactive nitrenium ion. Thus, the balance between toxification and detoxification...

Modeling Studies on Prediction of Putative Pharmacophores

Under selection from repeated sprays of insecticides, individuals possessing biochemical mechanisms that can detoxify the insecticide more rapidly or are less sensitive to it are likely to be favoured. These resistant insects survive doses that would kill normally sensitive individuals. Genes encoding these mechanisms will then be passed on to the succeeding generations, resulting in pest populations that are not controlled effectively. This can lead to farmers increasing the rate or frequency of applications, imposing further selection pressure and ultimately leading to a situation whereby the pests become totally immune. Removal of selection pressure may result in the pest populations regaining some degree of sensitivity, particularly if there is a fitness cost to resistance such as longer development times or reduced over-wintering ability. Usually, however, the population never regains the degree of sensitivity of the na ve population, and often there appears to be little fitness...

Figure 15 Structure of the cofactor undine5diphosphoaDglucuronic acid 39 UDPGA generic reactions of O and

An important pathway of O-glucuronidation is the formation of acyl-glucuronides (Figure 15a). Substrates are numerous nonsteroidal anti-inflammatory arylacetic and 2-arylpropionic acids (e.g., ketoprofen, 43 in Figure 16) and aliphatic acids (e.g., valproic acid, 44 in Figure 16). More recent drug classes such as statins and endothelin receptor antagonists may also yield acyl-glucuronides. Aromatic acids do not appear to be good substrates, but there are exceptions. The significance of acyl-glucuronides has long been underestimated. Indeed, these metabolites are quite reactive, rearranging to positional isomers and binding covalently to plasma and seemingly also tissue proteins.84,85 Thus, acyl-glucuronide formation cannot be viewed solely as a reaction of inactivation and detoxification.

Link between Metabolism and Safety 510431 Activity of metabolites

Historically, the selection of the large toxicological species using the in vitro interspecies comparison study performed with liver microsomes or hepatocytes was the major link between metabolism studies and safety (see 5.39 Computational Models to Predict Toxicity). Today, with the early identification of human metabolites, the question of their potential positive (pharmacological) or negative (toxicological) activity can be asked (see 5.08 Mechanisms of Toxification and Detoxification which Challenge Drug Candidates and Drugs).

Introduction 4111 Overview

Many P450 proteins are specialized in the metabolism of endogenous substrates (steroid hormones, lipids, etc.) but much of their notoriety has been associated with the metabolism or detoxification of xenobiotics (natural products, drugs, pesticides, etc.). In insects, they are involved in many cases of insecticide resistance. In well-studied cases, P450 enzymes generate more toxic compounds, e.g., carcinogenic metabolites of aryl hydrocarbons. Many foreign compounds, as well as endogenous metabolites, can induce the transcription of P450 genes through complex interactions with nuclear receptors and bHLH-PAS proteins, such as the Ah (aryl hydrocarbon) receptor of vertebrates. There are many excellent reviews and books clearly presenting the state of knowledge on P450s, generally with an emphasis on mammalian and bacterial enzymes (Omura et al., 1993 Schenkman and Greim, 1993 Ortiz de Montellano, 1995b). Reliance on the advances made in noninsect systems is both necessary and risky....

Deiodination of lodothyronines

A high degree of similarities has been demonstrated between the structures of the deiodinases and the reactions they catalyze 50 . Yet, there are also important differences in their catalytic properties (table 3 fig. 4). D1 catalyzes both outer and inner ring deiodination while D2 only outer ring and D3 inner ring deiodination, respectively 52 . In addition to deiodination, iodothyronines are metabolized by conjugation of the phenolic hydroxyl group with sulphate or glucoronic acid (so-called phase II detoxification reactions) 53, 54 . The purpose of this is to increase the water solubility of the substrates and thereby to

Recycling Of Intramitochondrial Coash

As well as recycling of intramitochondrial CoASH by citrate synthase, there are other routes via which CoASH can be recycled. These are indicated in Table 1. Firstly, the carnitine acyltransferases, coupled with carnitine-acylcarnitine translocase, can export acyl groups, thus recycling intramitochondrial CoASH. Secondly, acyl-CoA hydrolases can hydrolyse the thioester link directly. They have been shown to be active in recycling CoASH from medium and short chain acyl-CoAs during inhibition by hypo-glycin metabolites.35,38,39 As well as having a high Kmapp for acyl-CoA esters, medium acyl-CoA hydrolase is inhibited by CoASH, thus further limiting their action. Another important route both of detoxification and recycling of CoASH, is glycine conjugation by the matrix enzyme acyl-CoA glycine-N-acyltransferase, which has maximal activity towards aromatic acyl-CoA esters and is the route of appearance of hippuric acid.43 5 Finally, intramitochondrial acyl-CoA synthases are reversible so...

Cardiovascular System

Transient hypertension is noted in nearly 50 of alcoholics undergoing detoxification and is related to quantity of drinking and severity of other withdrawal symptoms. Epidemiological studies have demonstrated that alcohol elevates blood pressure independently of age, body weight, or cigarette smoking (Klatsky, Friedman, & Armstrong, 1986). A 10-year follow-up study found even moderate intake of alcohol (< 23 grams day) significantly increased the risk for hypertension in men, independent of age and body mass index. The risk of hypertension was increased for women, but not significantly, when age and body mass index were controlled (Ohmori et al., 2002).

Function of the Gastrointestinal Tract

Together with the bile secreted by the liver, excretory products (e.g., bilirubin) reach the stool. The liver has numerous additional metabolic functions it is the obligatory intermediate station for almost all substances absorbed from the small intestine, and it is able to detoxify numerous foreign substances and metabolic end-products and to bring about their excretion.

[KLOHnihdeen Pregnancy Category C

Epidural use causes analgesia at presynaptic and postjunctional al-pha-2-adrenergic receptors in the spinal cord due to prevention of pain signal transmission to the brain. tv2, distribution, epidural 19 min elimination 22 hr. Uses Oral, Transdermal Mild to moderate hypertension. A diuretic or other antihypertensive drugs, or both, are often used concomitantly. Non-FDA Approved Uses Alcohol withdrawal, atrial fibrillation, attention deficit hyperactivity disorder, constitutional growth delay in children, cyclosporine-associated nephro-toxicity, diabetic diarrhea, Gilles de la Tourette's syndrome, hyperhidrosis, hypertensive emergencies, mania, menopausal flushing, opiate detoxification, diagnosis of pheochromocy-toma, postherpetic neuralgia, psychosis in schizophrenia, reduce allergen-induced inflammatory reactions in extrinsic asthma, restless leg syndrome, facilitate smoking cessation, ulcerative colitis.

Adenosine Deaminase

Complete medium supplemented with 10 g ml thymidine, 15 g ml hypoxanthine, 4 M 9-P-D-xylofuranosyl adenine (Xyl-A), and 0.01 to 0.3 M 2'-deoxycoformycin (dCF). FCS contains low levels of ADA which will detoxify the medium, so serum should be added immediately prior to use. Basis for selection. Xyl-A can be converted to Xyl-ATP and incorporated into nucleic acids, resulting in cell death. Xyl-A is detoxified to its inosine derivative by ADA. dCF is a transition state analogue inhibitor of ADA, and is needed to inactivate ADA endoge

Critical Parameters

To produce stable cell lines, it is obviously necessary that the selective marker be expressed at a level adequate to detoxify the selective drug. This is most easily accomplished using TK as a marker when transfect-ing TK- cells, or when using any bacterial gene (APH, XGPRT, or HPH) as a dominant selectable marker. This is because the recipient cells contain no endogenous gene that detoxifies the selective drugs, so a small level of synthesis from the transfected gene will give the transfected cells a significant advantage over the parental cells. This is much harder to accomplish when using DHFR or ADA to transfect a normal cell type. Mammalian cells can have fairly high endogenous levels of ADA and DHFR, and therefore extremely high levels of expression

Indoxacarb and Insecticide Resistance

As has been mentioned, certain field strains of C. rosaceana, which have developed resistance to many conventional insecticides, are also poorly sensitive to indoxacarb (Ahmad et al., 2002). This may be due to an enhanced ability to detoxify indoxa-carb however, this insect is not on the indoxacarb US label and is an extremely unusual example of such poor susceptibility in Lepidoptera.

Treatment And Management Of Substance Use Disorders

The initial phase of addiction treatment is usually concerned with providing safe and humane detoxification from the substance of abuse. Benzodiazepines are recommended as the treatment of choice in management of alcohol or sedative hypnotic withdrawal (Mayo-Smith, 1997), although some clinicians have also advocated the use of anticonvulsants (Pages and Ries, 1998 Malcolm et al., 2001). Detoxification can generally be done at the same dosages as those for seronegative patients until the later stages of HIV illness, when lower doses may be necessary. Methadone detoxification is the preferred method of managing opioid withdrawal. Schedules using bu-prenorphine and or clonidine for opioid detoxification are also available (NIH Consensus Development Conference, 1998). Detoxification from cocaine and stimulants is not done pharmacologically. After medical stabilization and detoxification, the goals of treatment should include maintenance of abstinence when possible and rapid treatment of...

Psychosocial Treatments

L., Bigelow, G. E., Liebson, I. A., Jasinski, D. R., & Johnson, R. E. (1988). A clinical trial of buprenorphine Comparison with methadone in the detoxification of heroin addicts. Clin Pharmacol Ther, 43, 72-78. Cheskin, L. J., Fudala, P. J., & Johnson, R. E. (1994). A controlled comparison of buprenorphine and clonidine for acute detoxification from opioids. Drug Alcohol Depend, 36, 115-121. Hensel, M., & Kox, W. J. (2000). Safety, efficacy, and long-term results of a modified version of rapid opiate detoxification under general anesthesia A prospective study in methadone, heroin, codeine, and morphine addicts. Acta Anaesthsiol Scand, 44(3), 326-333. Kleber, H. D., Riordan, C. E., Rounsaville, B., Kosten, T., Charney, D., Gaspari, J., et al. (1985). Clonidine in outpatient detoxification from methadone maintenance. Arch Gen Psychiatry, 42, 391-394. O'Connor, P. G., Waugh, M. E., Carroll, K. M., Rounsaville, B. J., Diagkogiannis, I. A., &...

Resistance Mechanisms

Insects detoxify pyrethroids at varying rates and this degradative metabolism is important in understanding the detailed toxicology. Indeed, part of the relatively modest insecticidal activity of the natural pyrethrins is attributable to their rapid metabolic breakdown. Consequently, household sprays are usually formulated with synergists that inhibit the enzymes that catalyze this metabolic degradation and thereby enhance the insecticidal activity. Selection of insect strains possessing elevated levels of catabolizing enzymes is also an important mechanism in the development of decreased sensitivity (resistance) toward pyrethroids. There are two principal routes of detoxification of pyrethroids in insects de-esterification catalysed by both esterases and cytochromes P450, and the hydroxylation of molecule is detoxified are shown in Figure 5. The width of the arrow indicates the approximate extent of metabolic attack. It is in the detailed enzymology and molecular biology of the...

UDPglucuronosyltransferases EC 24117

Conjugation with glucuronic acid is the most abundant phase-II reaction (see 5.06 Principles of Drug Metabolism 2 Hydrolysis and Conjugation Reactions). UDP-glucuronosyltransferases (UGTs)52 catalyze the formation of beta-D-glucuronides from a large variety of xenobiotics by their reaction with UDP-glucuronic acid (UDPGA). Hydroxyl-, thiol-, amino-, hydroxylamino- and carboxyl-substituents serve as the anchor to which glucuronic acid can be conjugated (also C-glucuronides can be formed if the hydrogen of the respective C-H bond is sufficiently mobile such as a carbon atom between two carbonyl functions). The xenobiotic substituents engaged in the glucuronic acid conjugation are nucleophilic. Accordingly, the majority of the UGT substrates are not genotoxic. The anchor groups listed above are often determinants or co-determinants of the biological activity of drugs and toxins, since they are frequently involved in the interaction with receptors or enzymes. Therefore, conjugation of...

Bracken fern Pteridium aquilinum Dennstaedtiaceae

In the past in many parts of the world, the rhizome was ground and added to flour to bake bread. In the Canary Isles (La Palma and La Gomera) up to the 1930s the rhizomes were ground and mixed with barley meal to prepare a kind of porridge called gofio. It is the young shoots of the plant that are important in Japanese and Korean cooking the shoots are soaked for a day in water and ashes (an archaic detoxification method), then steamed or boiled and eaten as a vegetable or in soups. Sometimes the shoots are preserved in salt, in lees of sake or in miso. Bracken fern shoots have also been used in Siberia to produce a kind of beer, and by native peoples in North America. Leaves are commonly used by shepherds in the Mediterranean to filter sheep's milk and to store freshly made ricotta cheese.

Assessment of In Vitro Skin Metabolism

Metabolism of a xenobiotic is a detoxification and elimination process involving formation of molecules that are more hydrophilic and easily excreted. It can be summarized as a two-phase process. The first stage is the exposure or addition of functional groups to form a primary product by, for example, the production of free hydroxyl, carboxyl, or amino groups. The second step usually involves conjugation with a polar molecule (e.g., glucuronic acid) to form hydrophilic compounds that are readily excreted (109). It is widely established that there is potential for biotrans-

Epoxide hydrolases EC 3323

Epoxide hydrolases (EHs)38 catalyze the hydrolytic cleavage of oxirane rings. Because of the higher electron attracting force of the oxygen atom compared with the two carbon atoms of oxirane rings, epoxides possess two electrophilic carbon atoms, the electrophilic reactivity of which is enhanced by the tension of the three-membered oxirane ring. Depending on the influences of the rest of the molecule this can make epoxides highly cytotoxic, genotoxic, and carcinogenic. Therefore, the EH-catalyzed hydrolytic opening of oxirane rings is normally a detoxification reaction. Some important, and predictable, exceptions are discussed below. aspartate to form an enzyme-substrate ester that is hydrolyzed by a water molecule activated by proton abstraction through the histidine acidic amino acid pair. This releases the product, a vicinal (trans-, if applicable) diol, and restores free enzyme. While the second step of detoxification (hydrolysis of the enzyme-substrate ester to give the diol...

Dehydrogenases and reductases

Alcohol dehydrogenase (E.C. 1.1.1) (ADH)32 toxifies ethanol to acetaldehyde, which is then (predominantly) detoxified by an aldehyde dehydrogenase (E.C. 1.2.1) to acetic acid. The second step, the aldehyde dehydrogenase-mediated oxidation to acetic acid, is inhibited by disulfiram (Antabus), which is used in the treatment of alcohol addiction. After alcohol consumption disulfiram leads to the accumulation of the toxic acetaldehyde. The resulting toxicity provokes headache and nausea, which is intended to keep the alcoholic from further alcohol consumption. Many other aldehydes, such as the a,b-unsaturated aldehydes (lipid peroxidation products), are also markedly toxic. Thus, aldehyde dehydrogenase predominantly leads to detoxification. However, as is the case with all adequately investigated drug-metabolizing enzymes, aldehyde dehydrogenase plays a dual role with respect to toxification detoxification, the nature of which depends on the substrate in question. Methanol is metabolized...

Glutathione Sconjugates

Thus, the 10,11-epoxide and the 10,11-dihydrodiol are urinary metabolites in humans and rats given the drug. In epileptic patients, the range of plasma concentrations of the epoxide and the diol was approximately 0.8-17 mM and 0.8-36 mM, respectively, i.e., a predominance of the latter.33 A number of studies have also addressed the origin of toxic reactions seen in some patients, e.g., CNS symptoms, gastrointestinal and hepatic disturbances, and hypersensitivity. Whereas no single factor seems to account for such toxic effects, the pharmacologically active 10,11-epoxide appears to contribute to clinical toxicity.34 In this perspective, the EH-catalyzed hydrolysis of the epoxide appears as a reaction of detoxification.

Cognitive Behavioral and Nonpharmacological Treatments

Tity is considered unimportant, patients are less likely to manifest overt resistance. Rather than emphasize powerlessness, this approach assumes that people have within themselves the capacity to change. Although the efficacy of MET MI for cocaine abusers has yet to be proven, it would appear that its unique focus on readiness should, at minimum, help patients to engage in other forms of therapy. In addition, a few studies have begun to support the use of MET MI for treatment of cocaine abuse and dependence. In a small study examining 27 female workers with concurrent cocaine or heroin dependence, MI significantly reduced the women's cocaine use (Yahne, Miller, Irvin-Vitela, & Tonigan, 2002). Similarly, compared to patients who only underwent a detoxification program, patients who also received MI were more likely to be abstinent from cocaine following detoxification and demonstrated higher abstinence rates throughout the following relapse prevention treatment. In addition, MI was...

The Neurobiology of Substance Dependence

Brain abnormalities resulting from chronic use of nicotine, stimulants, opioids, alcohol, hallucinogens, inhalants, cannabis, and many other abused substances are underlying causes of dependence (the need to keep taking drugs to avoid a withdrawal syndrome) and addiction (intense drug craving and compulsive use). Most of the abnormalities associated with dependence resolve after detoxification, within days or weeks after the substance use stops. The abnormalities that produce addiction, however, are more wide-ranging, complex, and long-lasting. They may involve an interaction of environmental effects for example, stress, the social context of initial opiate use, and psychological conditioning and a genetic predisposition in the form of brain pathways that were abnormal even before the first dose of opioid was taken. Such abnormalities can produce craving that leads to relapse months or years after the individual is no longer opioid-dependent.

Delayed Manifestations

CNS neurotoxicity predominates Confined to basal ganglia globus pallidus, putamen, hippocampus (CT confirmation) resulting in toxic parkinsonism, with bradykinesia, dystonia, dysarthria, no rigidity (L-dopa resistant). Chronic low-level cyanide toxicity occurs in (1) Tobacco amblyopia (male smokers) (2) tropical (cassava root) ataxic neuropathy, (3) Leber's hereditary optic atrophy (males). Mechanism low endogenous stores of CN-detoxify-ing hydroxocobalamin and thiosulfate. Results from depletion of detoxifying substances by chronic low-grade CN poisoning from cigarette smoking (tobacco amblyopia and Leber's heredity optic atrophy) or frequent cassava root ingestion (tropical ataxic neuropathy).

Host Plant Induction and Pesticides

Treatment with 2-tridecanone, a toxic allelo-chemical from trichomes of wild tomato, protects H. zea larvae against carbaryl toxicity (Kennedy, 1984) and H. virescens larvae against diazinon toxicity (Riskallah etal., 1986b). In H. virescens larvae, the compound caused both qualitative and quantitative changes in P450 spectral properties (Riskallah et al., 1986a), an induction confirmed by its effect on specific P450 genes in the gut of M. sexta larvae (Snyder et al., 1995 Stevens et al., 2000). Larvae of H. virescens with a genetic resistance to 2-trideca-none have increased P450 levels and P450 marker activities (benzphetamine demethylation, benzo a -pyrene hydroxylation, phorate sulfoxidation), and these can be further increased by feeding 2-trideca-none (Rose et al., 1991). A laboratory population of H. zea can rapidly display increased tolerance to a-cypermethrin by selection of an increased P450 detoxification ability with a high dose of dietary xanthotoxin (Li et al., 2000b)....

Gender Ethnicracial And Life Span Considerations

Some patients may be misusing and abusing psychoactive drugs through ignorance. Others may have begun using them as part of a physician-prescribed treatment regimen and then became addicted. If the individual is unable to give a history because of overdose, friends or family members may provide needed information and clothing can be checked for drug paraphernalia. Elicit a history of previous detoxification treatments, effectiveness, length of recovery, and what influenced a return to drug usage.

The Challenges of Predicting Toxicity

The metabolic fate of a chemical, or the susceptibility of a compound to undergo biological transformations, can have a profound effect on its ability to cause toxicity. Often a drug compound itself can be benign, but can be metabolized to a reactive intermediate that can elicit a toxic response following exposure to the drug. In other instances, metabolism can lead to detoxification of a drug molecule. Kalgutkar et al.5 provide an extensive review of typical substructures that have been shown to be metabolized to reactive intermediates and have been associated with the expression of adverse drug reactions (ADRs). The problem occurs when the body runs out of glutathione. As glutathione stores are diminished, NAPQI is not detoxified, and covalently binds to the lipid bilayer of hepatocytes, causing centrilobular necrosis, resulting in hepatotoxicity. The maximum daily dose of paracetamol is 4 g in adults and 90 mgkg _ 1 in children. A single ingestion

Cns Targets For Hiv Infection

Astrocyte function, critical for the survival of neurons, may be impaired in the context of HIV-1 infection. Astrocytes are responsible for maintaining homeosta-sis in the CNS and are important in the detoxification of excess excitatory amino acids such as extracellular glutamate levels (Wesselingh and Thompson, 2001 Deshpande et al., 2005). However, infected astrocytes can produce cellular factors that may adversely affect neuronal survival (Lawrence and Major, 2002). Astrocytes play a dual role in the pathogenesis of HIV-related encephalopathy. In HIV-1 infection, astrocyte glutamate reuptake is impaired, possibly due to interactions with infected macrophages (Fine et al., 1996 Jiang et al., 2001). In addition, glutamate release from the astrocyte is induced by activated macrophages (Vesce et al., 1997 Bezzi et al., 2001). Activation of the CXCR4 receptor by stromal cell-derived factor 1 (SDF-1) results in the release of extracellular TNF-a and downstream release of glu

RCH2NR2R3 O2 H2O rcho hnr2r3 H2O2

(MPTP) is an interesting example of metabolism-related selective toxicity. It is toxified via the intermediate 1-methyl-4-phenyl-2,3-dihydropyridinium salt (MPDP +) to the 1-methyl-4-phenyl pyridinium salt (MPP+). MPP+ is taken up by a high-affinity reuptake system specifically localized in the nigrostriatal dopaminergic neurons and blocks their mitochondrial energy metabolism. This leads to death of these neurons, which causes Parkinson's disease. Within the neurons only MAO can metabolize MPTP, while in other tissues CYP- and FMO-catalyzed detoxification reactions compete with MAO for the substrate. This combination of selective uptake into cells possessing a selective pattern of drug-metabolizing enzymes causes the selective neurotoxicity. MPTP is an experimental chemical. Related compounds such as beta-carboline or tetrahydroisoquinoline are present at low concentrations in food. Whether they behave in a similar way to MPTP and therefore are neurotoxicologically important by...

Modeling of Phase 2 Metabolism Enzymes

GSTs catalyze the nucleophilic attack of the thiol of the tripeptide glutathione (GSH) on electrophilic substrates, a reaction usually resulting in addition or substitution, depending on the nature of the substrate.68 Many diverse compounds, including toxic xenobiotics and reactive products of intracellular processes such as lipid oxidation, act as GST substrates.69 The primary function of GST isoenzymes is generally considered to be detoxification of both endogenous and xenobiotic compounds.70,71 However, GSTs can also lead to the formation of more reactive intermediates, either directly or following conversion of glutathione conjugates by other biotransformation enzymes. In some cases the glutathione conjugates formed are labile, and dissociate to the parent electrophile in other tissues.71 Substrates for GSTs share three common features they are hydrophobic, contain an electrophilic atom, and also react nonenzymatically with GSH.68 Sulfate conjugation generally produces a highly...

Toxicogenomics Evolution Of The Field

Most toxicogenomics studies to date have involved hepatotoxicants 23,36, 38-44,47,49,50,52-55,57,59,60,204 , as the liver is the primary source of xenobiotic metabolism and detoxification and because liver injury is the principal reason for withdrawal of new drugs from the market 205 . Toxicogenomics studies have also addressed nephrotoxicity 44,45,51 , neurotoxicity 206,207 , reproductive toxicity 48 , as well as lung toxicity 39,56 , skin toxicity 208 , and cardio toxicity 209 . Expression profiles are altered by experimental conditions, including the harvest method, the in vitro culture method, and the vehicle used to deliver an agent, time of day of sacrifice, and diet. Up to 9 of the transcripts in mouse liver fluctuated with circadian cycling 216 . These included genes controlling glucose metabolism and vesicle trafficking or cytoskeleton, as might be anticipated from changes in the diet of animals during the day and night. In addition transcript levels of Cyp17 and Cyp2a4,...

Treatment Considerations

In the acute setting, multiple SUDs present the treatment team with significant challenges. Given a patient's complicated history of recent and chronic use of multiple substances, the clinician in the emergency room or detoxification unit often struggles to make treatment priorities out of a constellation of signs and symptoms that may be the result of intoxication or withdrawal from a number of substances. Given the frequent occurrence of multiple substance use diagnoses (particularly between alcohol and other drugs), any attempt to attribute observed findings associated with comorbid substance use to a single substance, or class of substances, is often difficult, if not impossible. Intoxication from stimulants may result in psychotic symptoms, but so does withdrawal from sedatives. Lethargy is not only a classic sign of opioid intoxication but also a consequence of stimulant withdrawal. A patient who currently uses both benzo-diazepines and crystal methamphetamine, and presents with...

Resistance Mechanism for Resistance and Resistance Potential

In some strains of S. littoralis, resistance to diflu-benzuron was also increased by a factor of about 300 (El-Guindy et al., 1983). El Saidy et al. (1989) reported that diflubenzuron and teflubenzuron were hydrolyzed rapidly by all tissues tested, and the gut wall was the most active tissue reaching 61 hydrolytic breakdown for diflubenzuron and 16 for teflubenzuron. Interestingly, profenofos and DEF could inhibit degradation of both BPUs tested under optimal conditions. Ishaaya and Casida (1980) had earlier reported that these organopho-sphorous compounds can inhibit insect esterases in larval gut integument. The strong synergism activity of DEF and profenofos indicated that the major route of detoxification in S. littoralis was through hydrolysis, while oxidative metabolism was found to be of minor importance for resistance. for the first time in Denmark, and some field populations with resistance to cyromazine. A fivefold cyromazine resistant strain was established and this was 3-,...

Discontinuation of Benzodiazepine

Discontinuation of sedatives and hypnotics, including the benzodiazepines, can be divided into three categories (1) long-term low-dose benzodiazepine use, (2) high-dose benzodiazepine abuse and multiple drug abuse, and (3) high-dose abuse of nonbenzodiazepine sedatives and hypnotics (especially intermediate-acting barbiturates). The first group of patients can usually be discontinued on an outpatient basis. Some of the second and even the third group can be treated as outpatients, but most will require inpatient care. Inpatient discontinuation today with managed care is generally reserved for patients who fail at outpatient discontinuation and for those who demonstrate acutely life-threatening loss of control over their drug use. The pharmacological management of inpatient benzodiazepine withdrawal from nontherapeutically high doses of these medicines is covered in standard texts dealing with inpatient detoxification (Wesson et al., 2003).

Metabolism

Drug metabolism is the phase of biochemical transformation of the drug. It is highly variable among drugs and depends on biological conditions. The metabolism phase is absent for the few drugs that are not transformed. As explained in great detail in other chapters (see 5.05 Principles of Drug Metabolism 1 Redox Reactions 5.06 Principles of Drug Metabolism 2 Hydrolysis and Conjugation Reactions 5.07 Principles of Drug Metabolism 3 Enzymes and Tissues 5.08 Mechanisms of Toxification and Detoxification which Challenge Drug Candidates and Drugs 5.09 Immuno-toxicology 5.10 In Vitro Studies of Drug Metabolism 5.33 Comprehensive Expert Systems to Predict Drug Metabolism 5.43 Metabonomics), biotransformations may involve one or more successive reactions From a physicochemical point of view, drug metabolism is expected to yield metabolites of lower lipophilicity relative to the parent drug, e.g., by adding an ionizable group. As a result, metabolites are often excreted faster than the parent...

Peroxisomes

In 1965, C. de Duve discovered peroxisomes in liver cells. J.A. Rhodin had pre-3 viously described them as microbodies. They are small, spherical organelles with a diameter of about 0.2-1.5 imm, which are ubiquitous in cells. Peroxisomes have a single membrane as their outer border. Their finely granular or homogeneous content is electron-dense. Occasionally, peroxisomes enclose paracrystalline materials. Peroxisomes are respiratory organelles. They contain various oxidases, catalase and the enzymes for the p-oxidation of fatty acids. Peroxisomes owe their name to their peroxidative enzyme content. They play an important role in the detoxification of cells. Example the enzyme catalase will split hydrogen peroxide, a lethal cell poison. Genetic diseases that are based on peroxisomal defects include Zellweger syndrome, Refsum syndrome and adrenoleukodystrophy (see textbooks of pathology and internal medicine).

Apap

NAC Supplies glutathione to detoxify NAPQI, effective up to 8 hours post overdose, possible up to 24 hours post ingestion can even reverse NAPQI binding to hepatocytes. NAC oral dosing Rule of 7s orally load 140 mg kg, administer 70 mg kg every 4 hours x 17 doses x 72 hours. Monitor APAP plasma levels every 4 hours.

Overview

In terms of their xenobiotic function, the drug-metabolizing enzymes can create or unmask hydrophilic moieties in such xenobiotics in order to facilitate their renal clearance (e.g., cytochrome P450 (P450), flavin-containing monooxygenase (FMO), esterases, glucuronyltransferases, sulfotransferases), or they can detoxify electrophilic species that may be damaging to the cell (e.g., epoxide hydrolase, carbonyl reductases and glutathione (GSH) transferases). This enzymatic division is not a strict one, as certain oxidative P450 reactions and conjugation reactions, for example, can be viewed as bioactivation processes that convert a relatively benign compound into a more reactive species.2 Regardless, these diverse proteins can be divided operationally into three main categories (1) redox enzymes, that catalyze oxidation and reduction reactions (2) hydrolases, that catalyze reaction of water with esters, amides, and epoxides and (3) transferases, that conjugate xenobiotics with relatively...

Emotion

For psychopathological symptoms to dissipate in conjunction with abstinence from alcohol and drugs following the initial period of detoxification and withdrawal. Furthermore, it is essential to recognize that emotional distress can both precipitate and sustain a psychopathological disorder. Characterizing the client's emotional status therefore enables the clinician to determine the relation of psychopathology to substance abuse either as a predisposing condition, a correlate of the disorder, or a consequence of the disorder.

Cooh

As their name implies, small organic anions (300-500 Da) possess a net negative charge at physiological pH and their transepithelial transport into the negatively charged environment of the cell requires energy. This is largely to the OATs (SLC22 family) that are found mainly in cells playing a critical role in the excretion and detoxification of xenobiotics. The OAT family contains six members (OAT1, OAT2, OAT3, OAT4, OAT5, and URAT1), present mainly in the liver, kidney, placenta, brain capillaries, and choroid plexus (Table 4). Their topological structures are very similar to those of the OCTs (Figure 6), but they have more complex energy requirements.94 The members of the OAT1, OAT2, and OAT3 group form a tertiary active system, with the first driving element being a Na + gradient furnished by the Na +, The OAT proteins play a critical role in the excretion and detoxification of a wide variety of drugs, toxins, hormones, and neurotransmitter metabolites. Uremic toxins, which...

Species Differences

It is important to choose the appropriate animal species for the analysis of the metabolism of a drug, in order to make predictions for metabolism-dependent toxicities in man. An impressive example of wrong predictions concerning toxification versus detoxification was the use of cynomolgus monkeys as an animal species closely related to man in the assessment of the carcinogenicity of heterocyclic amines present in cooked meat. Cynomolgus monkeys do not possess the heterocyclic amine toxifying CYP1A2. Thus, the study gave false-negative results. In contrast, these heterocyclic amines were potent carcinogens in the marmoset, a primate with a significant level of CYP1A2.

Treatment Method

Colon therapy is claimed to be beneficial because it involves detoxification. It is believed that waste material on the walls of the intestine is toxic and that this material is absorbed into the bloodstream and produces disease. This toxic material is removed through colonic irrigation, and beneficial effects are allegedly produced.

Induction

Induction has been defined as an increased level of enzyme gene expression (see 5.08 Mechanisms of Toxification and Detoxification which Challenge Drug Candidates and Drugs), and hence an increase in enzyme activity, resulting from exposure to a xenobiotic or endogenous components.87

Other hydrolases

Glutathione (GSH) and glutathione S-transferases (GSTs)48 represent the prime defense system against elec-trophile-mediated drug toxicity in mammals However, as is the case with all adequately investigated drug-metabolizing enzymes, GSTs in some predictable cases act as toxifying enzymes and glutathione is itself mutagenic when activated by rat kidney homogenates (S9).49 The 'normal' detoxifying role of GSTs is due to the fact that they detoxify lipophilic and structurally very diverse electrophiles by conjugating them with the endogenous hydrophilic nucleophile glutathione. This neutralizes the electrophilic reactivity and renders the compound easily excretable.1 Glutathione conjugates are released from the cells by an active transport system that belongs to the multidrug resistance (MDR) protein complex. Since the GSTs are often strongly product-inhibited this active removal of the products is important for the efficiency of GST-mediated detoxification.50 Nucleophilic addition of...

Withdrawal

The opioid withdrawal syndrome can easily be suppressed by administering any opioid with significant same-receptor agonism as the drug that originally produced the addiction. However, it is more useful to prevent opioid withdrawal symptoms pharmacologically with a nonaddicting drug. This approach furthers the goals of detoxification and abstinence. When circumstances force addicts to treat their withdrawal symptoms without opioids, they most commonly use alcohol and or benzodiazepines. The main disadvantage to this approach is that because of the lack of cross-tolerance between opioids and alcohol benzo-diazepines, blockade of withdrawal symptoms requires the ingestion of large amounts of these sedatives to achieve suppression. Clonidine, a presynaptic alpha2 agonist originally marketed as an antihypertensive, represents an effective and safer alternative for the treatment of opiate withdrawal symptoms (Koob & Bloom, 1988 O'Connor et al., 1995). It can partially suppress many (but...

Maintenance

After detoxification, relapse prevention must be actively addressed with whatever treatment interventions are available. Unfortunately, a large percentage of addicts seem unable to tolerate acute withdrawal, to succeed at controlled detoxification, or to remain drug free. Methadone maintenance may then become the treatment of choice. Administered on a once-a-day schedule, methadone in appropriate doses blocks opioid withdrawal, thus reducing compulsive drug-seeking behavior and use. The individual may then focus energy and attention on more productive behaviors. Indications for the use of methadone maintenance include (1) a history of chronic, high-dose opioid abuse (2) repeated failures at abstinence (3) history of prior successful methadone maintenance (4) history of drug-related criminal convictions or incarcerations (5) pregnancy, especially first and third trimesters and (6) HIV seropositivity. Some individuals report that heavy labor with much perspiration reduces the...

Integration Of Data

Despite the numerous successes of toxicogenomics in the context of toxicology, a poorly addressed but confounding issue pertinent to drug safety and human risk assessment is the impact of the individual genetic background on the response of the individual animal or human patient. The PharmGKB pharmacogenetics knowledgebase 143 cataloges the different human genetic backgrounds by their susceptibility to drug therapy. In addition the NIEHS Environmental Genome Project (EGP 24 ) is identifying SNPs in genes that are important in environmental disease, detoxification, and repair. Linkages of toxicogenomics knowledgebases with those containing information about SNPs and human susceptibility will gradually lead to a more complete picture of the relevance of the responses and genotypes of surrogate animal species to human risk assessment.

Bn80927

Tafluposide (F11872) (33) is a novel phosphate prodrug of a lipophilic, perfluorinated epipodophyllotoxin, and is an example where significant modification of a topo II inhibitor has altered its spectrum of enzyme activity. Tafluposide has superior antitumor activity in vivo compared to etoposide.176 Although it does not inhibit the religation step of the catalytic cycle of either topo I or topo II, it is a potent inhibitor of the catalytic activities of both enzymes. It does not bind to DNA, but inhibits the binding of the enzymes to DNA in a drug- and enzyme-dependent manner177 and possibly represents a new class of topoisomerase agent. A resistant P388 leukemia subline retained marked collateral sensitivity to cisplatin, topotecan, colchicine, and Vinca alkaloids, with no overexpression of resistance-related proteins or modification of the glutathione-mediated detoxification process. However, nucleotide excision repair activity was decreased threefold, suggesting that both...

Heavy Metals

Heavy metals are the higher molecular weight metallic elements. Most are needed in trace amounts by biological systems for homeostatic functioning, but are toxic at higher concentrations. Heavy metals are a common byproduct of industrial processes resulting in environmental contamination where the metals can persist for long periods of time. Heavy metals are a health concern because they accumulate to high levels in body tissues as detoxification and elimination rates are low. Once heavy metals accumulate in tissues, biomagnification can occur resulting in increasing concentration of a substance as one travels up the food chain. As a result, humans can potentially be exposed to highly toxic concentrations of heavy metals through their diet.

Endocrine System

Thyroid dysfunction is common in alcoholics. Consistent findings indicate reduced thyroxine, and total and free triodothyronine concentrations in early abstinence. A blunted thyroid stimulation test is found in one-third of alcoholics during detoxification and into the early weeks of abstinence. A direct toxic effect of alcohol on the thyroid is likely, which in turn induces a compensatory activation of the hypothalamic-pituitary (HP) axis (Hermann, Heinz, & Mann, 2002).

Detoxification and Weight Loss

Detoxification and Weight Loss

Detoxification is something that is very important to the body, but it is something that isn't understood well. Centuries ago, health masters in the East understood the importance of balancing and detoxifying the body. It's something that Western medicine is only beginning to understand.

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