Mercapturic acid epoxide intermediate

Following oral administration of 50 mg/kg bw 2,3-dibromopropan-l-ol to male Sprague-Dawley rats, two urinary mercapturic acid metabolites were identified as N-acetyl-5 -(2,3-dihydroxypropyl)cysteine and A, W-bis-acetyl-N<5"-(l,3-bis-cysteinyl)-propan-2-ol, respectively. It was inferred that 3-bromo-l,2-propane epoxide is an intermediate in the metabolism of 2,3-dibromopropan-l-ol. In addition, (3-bromolactate was produced, presumably as a result of hydrolysis to the a-bromohydrin and subsequent oxidation (Jones Fakhouri, 1979). Marsden and Casida (1982) identified small amounts of 2-bromoacrylic acid in the urine of rats injected intraperitoneally with 2,3-dibromopropan-l-ol and suggested that this arose by oxidation and dehydrobromi-nation, with 2-bromoacrolein as an unstable intermediate. 

The oxidation of naphthalene was one of the earliest examples of an epoxide as an intermediate in aromatic hydroxylation. As shown in Figure 7.3, the epoxide can rearrange nonenzymatically to yield predominantly 1-naphthol, or interact with the enzyme epoxide hydrolase to yield the dihydrodiol, or interact with glutathione S-transferase to yield the glutathione conjugate, which is ultimately metabolized to a mercapturic acid. These reactions are also of importance in the metabolism of other xenobiotics that contain an aromatic nucleus, such as the insecticide carbaryl and the carcinogen benzo(a)pyrene. 

Traditionally, the hydroxylation of aromatic compounds by CYP450 has been considered to be mediated by an arene oxide (epoxide) intermediate followed by the NIH shift," as discussed previously (29,30,31) (Fig. 10.6). The formation of phenols and fhe isolation of urinary dihydrodiols, catechols, and glutathione conjugates (mercapturic acid derivatives) implicates arene oxides as intermediates in the metabolism of benzene and substituted benzenes in mammalian systems. The arene oxides... 

This microsomal pathway results in the formation of products which may be stable, may undergo structural rearrangement to fonn phenols, or in the presence of a microsomal hydrase may be converted to dihydrodiols. Epoxides are also intermediates in the foimation of many mercapturic acids. 

The production of an epoxide intermediate provides a mechanism for tlie formation of premercapturic acids. These conjugates are true metabolic products of aromatic hj droearbons, the mercapturic acids being artifacts produced in the isolation procedures. 

---