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 via formaldehyde to formic acid. Although formaldehyde is also considerably toxic, the decisive toxic metabolite is formic acid, leading to edema of the retina, blindness, and death. Remarkably, ethanol is an effective antidote, since it has a much higher affinity for the ADH compared with methanol. A relatively high concentration of ethanol inhibits the dehydrogenation of methanol allowing for the excretion of unmetabolized methanol thereby preventing the toxification to formic acid.1
ADH is a member of the family of medium-chain alcohol dehydrogenases.32 The major function of most short-chain alcohol dehydrogenases32 in mammals is steroid metabolism. Nevertheless, many of them play important roles in drug toxification and detoxification. The 3a-hydroxysteroid dehydrogenase (3a-HSD) of rat and man oxidizes vicinal dihydrodiols of polycyclic aromatic hydrocarbons to catechols and these to quinones.33 Hence, 3a-HSD is also called dihydrodiol dehydrogenase. This reaction sequesters the pre-bay dihydrodiols of polycyclic aromatic hydrocarbons away from their critical toxification pathway to the ultimate carcinogenic dihydrodiol bay-region epoxides to produce instead the much less toxic catechols33 (Figure 3). In addition, it inactivates the highly mutagenic and carcinogenic bay region diol epoxides.34 Both of these reactions are protective, but the formation of catechols, which are further oxidized to quinones, is on the other hand also a potential toxification, since quinones frequently undergo redox cycling producing toxic reactive oxygen species. Thus, as usual for drug-metabolizing enzymes, with respect to toxification/detoxification the dihydrodiol dehydrogenase plays a dual role, the nature of which depends on the substrate. Toxification by dihydrodiol dehydrogenase occurs by catechol formation from naphthalene 1,2-dihydrodiol leading to naphthalene-induced cataract formation. In rabbit liver, at least eight enzymes possess dihydrodiol dehydrogenase activity. In rat liver only the 3a-HSD possesses dihydrodiol dehydrogenase activity.35 This is an interesting example of enzymes of endogenous function in some but not all species having acquired the ability to toxify/detoxify xenobiotics.
The 11b-hydroxysteroid dehydrogenase (11^-HSD) can also metabolize drugs, acting as a carbonyl reductase.36 The toxification of 4-(methylnitrosamino)-1-(3-pyridyl)-butan-1-one (NNK), a tobacco-specific nitrosamine, to the ultimate mutagenic metabolite can be prevented by 11^-HSD-catalyzed reduction of the keto function followed by conjugation to glucuronic acid.36
Similarly, the dimeric flavoprotein NAD(P)H quinone oxidoreductase (NQOR; E.C. 220.127.116.11) (also called DT-diaphorase) protects against the toxicity of quinones by their reduction to catechols followed by their conjugation and excretion. Two NQORs are known. NQOR-1 is induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; also called 'dioxin'). The NQOR works by an interesting 'ordered ping-pong' mechanism. First, an enzyme-cofactor complex is formed, leading to the reduction of the prosthetic group. NADH and NADPH can serve as reducing cofactors. After dissociation of the enzyme-cofactor complex the substrate binds, is reduced, and the product is released. Therefore, the enzymatic reaction can be inhibited by high concentrations of the substrate or the cofactor. Coumarin derivatives, such as warfarin, are naturally occurring inhibitors.
There are important species differences in the relevance of NQORfor drug metabolism and protection against their toxicities. In the rat NQOR is by far the most important enzyme for the reduction of many quinones. In man, however, a less specific carbonyl reductase is quantitatively of much higher importance.37 This represents an important difference for extrapolations between these species.
NQOR acts on its substrate by a two-electron transfer mechanism. It thereby circumvents the formation of the highly reactive semiquinone radicals from quinones. In this respect NQOR is protective against drug toxicity. On the other hand, NQOR reduces aromatic nitro compounds to aromatic hydroxyl amines, precursors of highly genotoxic reactive esters. Again, with respect to toxification/detoxification NQOR plays a dual role, the nature of which depends on the substrate and can easily be predicted, which is helpful for extrapolations between species.1
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