Cyp3a4

Multiple, constitutively very low in liver Liver

Liver Liver

Liver

Liver, kidney

Liver

Liver

Liver, gastrointestinal tract

Liver, small intestine

Polycyclic aromatic hydrocarbons (PAH)

Aromatic amines, PAH, aflatoxin Bi, phenacetin, acetaminophen, caffeine, warfarin, imipramine 6-Aminochrysene, aflatoxin Bi, nitrosamines, coumarin Cyclophosphamide, nicotine

Taxol, retinoids

Diclofenac, ibuprofen, phenytoin, tolbutamide

(S)-Mephenytoin, omeprazole

Debrisoquin, propranolol, dextromethorphan

Ethanol, benzene, dimethylnitrosamine, chlorzoxazone

Aflatoxin B1> acetaminophen, benzphetamine, nifedipine, steroid hormones, erythromycin

Orthologous forms with similar biochemical characteristics in different vertebrates Orthologous forms with similar biochemical characteristics in different vertebrates No clear relationship to a specific animal CYP In contrast to the rat CYP2B1 that is strongly inducible by, e.g., phenobarbital and thereby becoming a major hepatic CYP in this species, CYP2B6 has been found only in rather small amounts in human liver and does not seem to play an important role in the metabolism of most drugs

No clear relationship to a specific animal CYP No clear relationship to a specific animal CYP No clear relationship to a specific animal CYP No clear relationship to a specific animal CYP Orthologous enzymes in different species. Only one enzyme in the subfamily in humans and in many animal species Several very closely related isoenzymes in man (CYP3A3, CYP3A5, and CYP3A7) make it impossible to assign orthologous forms in other species; otherwise, the biochemical characteristics resemble those of animal CYP3A isoenzymes

Reproduced from Oesch, F.; Arand, M. Xenobiotic Metabolism. In Toxicology; Marquardt, H., Schäfer, S. G., McClellan, R., Welsch, F., Eds.; Academic Press: New York, 1999, pp 83-109, with permission from Elsevier. a Primarily identified in the indicated organ, but possibly also expressed in other locations.

In the CYP2 family the isoenzymes of major toxicological interest in human are CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. The expression of CYP2A620 in human liver is modest (less than 5% of total CYP). This CYP can toxify the important human hepatocarcinogen aflatoxin B1 (with high affinity but low capacity), as well as some tobacco-specific nitrosamines and some carcinogenic aromatic amines such as 6-aminochrysene. Coumarin can serve as an in vivo probe substrate. Its 7-hydroxylation is selectively catalyzed by CYP2A6.20

CYP2B family membersii,2i are important in many experimental animal species such as the rat and rabbit. However, the only human CYP2B member known, CYP2B6, is expressed at a very low level in the liver and appears to be of limited importance in drug metabolism. One important substrate is the cytostatic drug cyclophosphamide, which is toxified by the human CYP2B6.22 Inactivation of CYP2B by cAMP-mediated phosphorylation substantially changes the metabolism of cyclophosphamide and its consequent toxicity.23

Conversely, the CYP2C family members24 are highly important in human drug metabolism and apparently much more so than in rodents. They metabolize a large number of drugs (see 5.05 Principles of Drug Metabolism 1: Redox Reactions)

Dihydrodiol Epoxide

Benzo[a]pyrene-7,8-dihydrodiol-8-sulfate

Figure 3 Toxicologicaly important pathways of benzo[a]pyrene (BP) metabolism. BP is metabolized to many primary, secondary, and tertiary metabolites. Depicted is the toxification to the ultimate carcinogen BP-7,8-dihydrodiol-9,10-epoxide. First CYP-mediated oxidation leads to the 7,8-epoxide, which is then hydrolyzed by microsomal epoxide hydrolase to the 7,8-dihydrodiol. Now conjugation to glucuronic acid or sulfate, dehydrogenation to the catechol, and isomerization to the phenol (not shown) compete with the final toxification to the 7,8-dihydrodiol 9,10-epoxide catalyzed by CYP or prostaglandin synthase (COX). The diol epoxide is a highly mutagenic compound that is not a substrate for epoxide hydrolase. Conjugation to glutathione leads to detoxification, but is not fast enough to abolish the genotoxicity. (Reproduced from Oesch, F.; Arand, M. Xenobiotic Metabolism. In Toxicology; Marquardt, H., Schafer, S. G., McClellan, R., Welsch, F., Eds.; Academic Press: New York, 1999, pp 83-109, with permission from Elsevier.)

Benzo[a]pyrene-7,8-dihydrodiol-8-sulfate

Figure 3 Toxicologicaly important pathways of benzo[a]pyrene (BP) metabolism. BP is metabolized to many primary, secondary, and tertiary metabolites. Depicted is the toxification to the ultimate carcinogen BP-7,8-dihydrodiol-9,10-epoxide. First CYP-mediated oxidation leads to the 7,8-epoxide, which is then hydrolyzed by microsomal epoxide hydrolase to the 7,8-dihydrodiol. Now conjugation to glucuronic acid or sulfate, dehydrogenation to the catechol, and isomerization to the phenol (not shown) compete with the final toxification to the 7,8-dihydrodiol 9,10-epoxide catalyzed by CYP or prostaglandin synthase (COX). The diol epoxide is a highly mutagenic compound that is not a substrate for epoxide hydrolase. Conjugation to glutathione leads to detoxification, but is not fast enough to abolish the genotoxicity. (Reproduced from Oesch, F.; Arand, M. Xenobiotic Metabolism. In Toxicology; Marquardt, H., Schafer, S. G., McClellan, R., Welsch, F., Eds.; Academic Press: New York, 1999, pp 83-109, with permission from Elsevier.)

CYP2D625'26 is especially important in humans because of its highly relevant polymorphism, which is due to: (1) inactive and less active alleles resulting in poor metabolizers; and (2) gene amplification of active alleles resulting in ultrarapid metabolizers. CYP2D6 metabolizes many drugs that have a basic nitrogen atom at a distance of 5-7 A from an easily oxidizable atom. Lack of CYP2D6 activity can lead to accumulation of highly toxic levels of these drugs. About 7% of the Caucasian population have a defective CYP2D6 gene and must be aware of potentially toxic effects caused by standard doses of drugs that are predominantly metabolized by CYP2D6 and have a narrow therapeutic window. There are correlations between CYP2D6 genotype and the incidence of certain forms of the parkinsonian syndrome, which can result from drug-induced toxicity to dopaminergic neurons in the central nervous system.

CYP2E127'28 metabolizes a wide array of substrates all of which have a relatively small molecular size. This includes therapeutic drugs such as acetaminophen, environmental carcinogens such as benzene, and several alkylnitrosamines, as well as the compound from which the letter of the family (E) is derived: ethanol. In the presence of inducer, most notably relatively high concentrations of substrate, the half-life of CYP2E1 is increased leading to an accumulation of enzyme protein. In several cases a concomitant stimulation of the transcription occurs. In some cases a stimulation of translation has also been reported. The heme iron of CYP2E1 is predominantly in a high spin state even in the absence of substrate, which is relatively unusual for CYPs. The consequence is that oxygen can bind to CYP2E1 also in the absence of substrate, which leads to the production of activated oxygen that is not used for substrate oxygenation. Thus, induced levels of liver CYP2E1 may lead to hepatotoxicity. Ethanol-induced liver injury may in considerable part be due to oxidative damage caused by increased levels of CYP2E1 as a consequence of the induction by ethanol. Conversely, phosphorylation of CYP2E1 mediated by cAMP and hence by drugs that lead to an increase in cAMP leads to CYP2E1 inactivation.29

The CYP3 family6'30 is the most important CYP family for the metabolism of therapeutic drugs. The most important member of the family is CYP3A4. It is usually the most abundant CYP in human liver (about 30% of the total CYPs). CYP3A4 has extraordinarily broad substrate specificity. This includes a great number of therapeutic drugs (see 5.05 Principles of Drug Metabolism 1: Redox Reactions), but also several carcinogens such as the important human hepatocarcinogen aflatoxin B1 (with high capacity but low affinity) as well as the metabolically formed key intermediary PAH-derived dihydrodiols, which it toxifies to the ultimate carcinogens the dihydrodiolepoxides. CYP3A4 is induced by rifampicin' dexamethasone' pregnenolone carbonitrile' and phenobarbital. The strong induction by rifampicin led to one of the most spectacular cases of drug interactions. The contraceptive steroids were metabolically inactivated as a consequence of CYP3A4 induction by the coincident treatment with rifampicin in tuberculosis patients to such an extent that a great number of unwanted pregnancies resulted.

Detox Diet Basics

Detox Diet Basics

Our internal organs, the colon, liver and intestines, help our bodies eliminate toxic and harmful  matter from our bloodstreams and tissues. Often, our systems become overloaded with waste. The very air we breathe, and all of its pollutants, build up in our bodies. Today’s over processed foods and environmental pollutants can easily overwhelm our delicate systems and cause toxic matter to build up in our bodies.

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  • anna toscani
    What contains benzo(a)pyrenes?
    5 years ago

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