METABOLISM OF TOXICANTS in VS .NET

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METABOLISM OF TOXICANTS
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(a) Nitro reduction CH3 N N CH3 NH2 N N H2N H3C
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S 2 (C2H5)2NCSH Dimethyldithiocarbamic acid
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(d ) Aldehyde reduction S O Cl S (C2H5)2PSCH2S Carbophenothion Cl
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(C2H5)2PSCH2S Carbophenothion sulfoxide
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(e) Sulfoxide reduction
Examples of metabolic reduction reactions.
sequences, the last reaction of which is catalyzed by glutathione reductase, using glutathione (GSH) as a cofactor: RSSR + GSH RSSG + RSH RSSG + GSH GSSG + RSH GSSG + NADPH + H+ 2GSH + NADP+
Ketone and Aldehyde Reduction. In addition to the reduction of aldehyde and ketones through the reverse reaction of alcohol dehydrogenase, a family of aldehyde reductases also reduces these compounds. These reductases are NADPH-dependent, cytoplasmic enzymes of low molecular weight and have been found in liver, brain, kidney, and other tissues.
PHASE I REACTIONS
Sulfoxide Reduction. The reduction of sulfoxides has been reported to occur in mammalian tissues. Soluble thioredoxin-dependent enzymes in the liver are responsible in some cases. It has been suggested that oxidation in the endoplasmic reticulum followed by reduction in the cytoplasm may be a form of recycling that could extend the in vivo half-life of certain toxicants.
Hydrolysis
Enzymes with carboxylesterase and amidases activity are widely distributed in the body, occurring in many tissues and in both microsomal and soluble fractions. They catalyze the following general reactions: RC(O)OR + H2 O RCOOH + HOR RC(O)NR R + H2 O RCOOH + HNR R RC(O)SR + H2 O RCOOH + HSR Carboxylester hydrolysis Carboxyamide hydrolysis Carboxythioester hydrolysis
Although carboxylesterases and amidases were thought to be different, no puri ed carboxylesterase has been found that does not have amidase activity toward the corresponding amide. Similarly enzymes puri ed on the basis of their amidase activity have been found to have esterase activity. Thus these two activities are now regarded as different manifestations of the same activity, speci city depending on the nature of R, R , and R groups and, to a lesser extent, on the atom (O, S, or N) adjacent to the carboxyl group. In view of the large number of esterases in many tissues and subcellular fractions, as well as the large number of substrates hydrolyzed by them, it is dif cult to derive a meaningful classi cation scheme. The division into A-, B-, and C- esterases on the basis of their behavior toward such phosphate triesters as paraoxon, rst devized by Aldridge, is still of some value, although not entirely satisfactory. A-esterases, also referred to as arylesterases, are distinguished by their ability to hydrolyze esters derived from aromatic compounds. Organophosphates, such as the insecticide paraoxon are often used to characterize this group. B-esterases, the largest and most important group, are inhibited by organophosphates. All the B-esterases have a serine residue in their active site that is phosphorylated by this inhibitor. This group includes a number of different enzymes and their isozymes, many of which have quite different substrate speci cities. For example, the group contains carboxylesterase, amidases, cholinesterases, monoacylglycerol lipases, and arylamidases. Many of these enzymes hydrolyze physiological (endogenous) substrates as well as xenobiotics. Several examples of their activity toward xenobiotic substrates are shown in Figure 7.13. C-esterases, or acetylesterases, are de ned as those esterases that prefer acetyl esters as substrates, and for which paraoxon serves as neither substrate nor inhibitor.
Epoxide Hydration
Epoxide rings of alkene and arene compounds are hydrated by enzymes known as epoxide hydrolases, the animal enzyme forming the corresponding trans-diols, although bacterial hydrolases are known that form cis-diols. Although, in general, the hydration
METABOLISM OF TOXICANTS
O (C2H5O)2PO NO2 + H2O
O (C2H5O)2POH + HO NO2
(a) A-Esterase O CH3CO + H2O O CH3COH + HO
O CH3CH2COCH3 + H2O O CH3CS O CH3CN H + H2O + H2O
O CH3CH2COH + CH3OH O CH3COH + SH
O CH3COH + NH2
(b) B-Esterase O CH3CO NO2 + H2O O CH3COH + HO NO2
(c) C-Esterase
Figure 7.13 Examples of esterase/amidase reactions involving xenobiotics.
of the oxirane ring results in detoxication of the very reactive epoxide, in some cases, such as benzo(a)pyrene, the hydration of an epoxide is the rst step in an activation sequence that ultimately yields highly toxic trans-dihydrodiol intermediates. In others, reactive epoxides are detoxi ed by both glutathione transferase and epoxide hydrolase. The reaction probably involves a nucleophilic attack by OH on the oxirane carbon. The most studied epoxide hydrolase is microsomal, and the enzyme has been puri ed from hepatic microsomes of several species. Although less well known, soluble epoxide hydrolases with different substrate speci cities have also been described. Examples of epoxide hydrolase reactions are shown in Figure 7.14.