Carbon-sulfur functional groups are susceptible to metabolic S-dealkylation, desulfuration, and S-oxidation reactions. The first two processes involve oxidative carbon-sulfur bond cleavage. S-dealkylation is analogous to O- and N-dealkylation mechanistically (i.e., it involves a-carbon hydroxylation) and has been observed for various sulfur xenobiotics.163,256 For example, 6-(methylthio)purine is demethylated oxidatively in rats to 6-mercaptopurine.257,258 S-demethylation of methitural259 and S-debenzylation of 2-benzylthio-5-trifluoromethyl-benzoic acid also have been reported. In contrast to O- and N-dealkylation, examples of drugs undergoing S-dealkyla-tion in humans are limited because of the small number of sulfur-containing medicinals and the competing metabolic S-oxidation processes (see diagram).
Oxidative conversion of carbon-sulfur double bonds (C=S) (thiono) to the corresponding carbon-oxygen double bond (C=O) is called desulfuration. A well-known drug example of this metabolic process is the biotransformation of thiopental to its corresponding oxygen analog pentobarbital.260,261 An analogous desulfuration reaction also occurs with the P=S moiety present in several organophosphate insecticides, such as parathion.262,263 Desulfuration of parathion leads to the formation of paraoxon, which is the active metabolite responsible for the anticholinesterase activity of the parent drug. The mechanistic details of desulfuration are poorly understood, but it appears to involve microsomal oxidation of the C=S or P=S double bond.264
Organosulfur xenobiotics commonly undergo S-oxida-tion to yield sulfoxide derivatives. Several phenothiazine derivatives are metabolized by this pathway. For example, both sulfur atoms present in thioridazine (Mellaril)265,266 are susceptible to S-oxidation. Oxidation of the 2-methylthio
6-(Methylthio)- 6-Mercaptopurine purine
6-(Methylthio)- 6-Mercaptopurine purine group yields the active sulfoxide metabolite mesoridazine. Interestingly, mesoridazine is twice as potent an antipsy-chotic agent as thioridazine in humans and has been introduced into clinical use as Serentil.267
S-oxidation constitutes an important pathway in the metabolism of the H2-histamine antagonists cimetidine (Tagamet)268 and metiamide.269 The corresponding sulfoxide derivatives are the major human urinary metabolites.
Sulfoxide drugs and metabolites may be further oxidized to sulfones (-SO2-). The sulfoxide group present in the immunosuppressive agent oxisuran is metabolized to a sulfone moiety.270 In humans, dimethylsulfoxide (DMSO) is found primarily in the urine as the oxidized product dimethylsul-fone. Sulfoxide metabolites, such as those of thioridazine, reportedly undergo further oxidation to their sulfone -SO2-
Many oxidative processes (e.g., benzylic, allylic, alicyclic, or aliphatic hydroxylation) generate alcohol or carbinol metabolites as intermediate products. If not conjugated, these alcohol products are further oxidized to aldehydes (if primary alcohols) or to ketones (if secondary alcohols). Aldehyde metabolites resulting from oxidation of primary alcohols or from oxidative deamination of primary aliphatic amines often undergo facile oxidation to generate polar car-boxylic acid derivatives.116 As a general rule, primary alcoholic groups and aldehyde functionalities are quite vulnerable to oxidation. Several drug examples in which primary alcohol metabolites and aldehyde metabolites are oxidized to carboxylic acid products are cited in previous sections.
Although secondary alcohols are susceptible to oxidation, this reaction is not often important because the reverse reaction, namely, reduction of the ketone back to the secondary alcohol, occurs quite readily. In addition, the secondary alcohol group, being polar and functionalized, is more likely to be conjugated than the ketone moiety.
The bioconversion of alcohols to aldehydes and ketones is catalyzed by soluble alcohol dehydrogenases present in the liver and other tissues. NAD+ is required as a coenzyme, although NADP+ also may serve as a coenzyme. The reaction catalyzed by alcohol dehydrogenase is reversible but often proceeds to the right because the aldehyde formed
is further oxidized to the acid. Several aldehyde dehydroge-nases, including aldehyde oxidase and xanthine oxidase, carry out the oxidation of aldehydes to their corresponding acids.116,271-273
Metabolism of cyclic amines to their lactam metabolites has been observed for various drugs (e.g., nicotine, phen-metrazine, and methylphenidate). It appears that soluble or microsomal dehydrogenase and oxidases are involved in oxidizing the carbinol group of the intermediate carbinolamine to a carbonyl moiety.273 For example, in the metabolism of medazepam to diazepam, the intermediate carbinolamine (2-hydroxymedazepam) undergoes oxidation of its 2-hydroxy group to a carbonyl moiety. A microsomal dehydrogenase carries out this oxidation.274
In addition to the many oxidative biotransformations discussed previously in this chapter, oxidative aromatization or dehydrogenation and oxidative dehalogenation reactions also occur. Metabolic aromatization has been reported for norgestrel. Aromatization or dehydrogenation of the A ring present in this steroid leads to the corresponding phenolic product 17a-ethinyl-18-homoestradiol as a minor metabolite in women.275 In mice, the terpene ring of A1-THC or A1,6-THC undergoes aromatization to give cannabinol.276,277
Many halogen-containing drugs and xenobiotics are metabolized by oxidative dehalogenation. For example, the volatile anesthetic agent halothane is metabolized principally to trifluoroacetic acid in humans.278,279 It has been postulated that this metabolite arises from CYP-mediated hydroxylation of halothane to form an initial carbinol intermediate that spontaneously eliminates hydrogen bromide (dehalogenation) to yield trifluoroacetyl chloride. The latter acyl chloride is chemically reactive and reacts rapidly with water to form trifluoroacetic acid. Alternatively, it can acylate tissue nucleophiles. Indeed, in vitro studies indicate that halothane is metabolized to a reactive intermediate (presumably trifluoroacetyl chloride), which covalently binds to liver microsomal proteins.280,281 Chloroform also appears to be metabolized oxidatively by a similar dehalogenation pathway to yield the chemically reactive species phosgene. Phosgene may be responsible for the hepatotoxicity and nephrotoxicity associated with chloroform.282
A final example of oxidative dehalogenation concerns the antibiotic chloramphenicol. In vitro studies have shown that the dichloroacetamide portion of the molecule undergoes oxidative dechlorination to yield a chemically reactive oxamyl chloride intermediate that can react with water to form the corresponding oxamic acid metabolite or can acylate microsomal proteins.283,284 Thus, it appears that in several instances, oxidative dehalogenation can lead to the formation of toxic and reactive acyl halide intermediates.
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