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The excretion of tetrachloroethene metabolites in urine was studied in occupationally exposed workers to identify and quantify metabolites formed by glutathione conjugation and by cytochrome P450 oxidation of tetrachloroethene in humans. The glutathione conjugation pathway has been implicated in the chronic toxicity and possible tumorigenicity of tetrachloroethene to the kidney in rats. The biosynthesis of S-(1,2,2-trichlorovinyl)glutathione and N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine in humans had not been demonstrated. In this study, we investigated the biotransformation of tetrachloroethene in humans occupationally exposed during dry cleaning. Tetrachloroethene concentrations in the air of the dry cleaning shop were 50 +/- 4 ppm; two individuals were exposed for 8 hr daily and two individuals were exposed for 4 hr daily. In urine samples collected from the individuals at the beginning and at the end of the work week, N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine and 2,2,2-trichloroethanol as tetrachloroethene metabolites in humans were identified by GC/MS. The concentrations of N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine in the urine of the individuals were not significantly different at the start and at the end of the work week; however, concentrations of both N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine and 2,2,2-trichloro compounds (trichloroacetic acid and 2,2,2-trichloroethanol) as a marker for cytochrome P450-mediated metabolism were proportional to the length of daily tetrachloroethene exposure. A remarkable difference in the excretion pattern of 2,2,2-trichloro compounds, the major tetrachloroethene metabolites, was observed. Trichloroacetic acid and 2,2,2-trichloroethanol were present in the urine of two of the exposed individuals. Only 2,2,2-trichloroethanol was identified as a major urinary tetrachloroethene metabolite in two other individuals who did not excrete detectable amounts of trichloroacetic acid. The obtained results indicate that humans also have the ability to biosynthesize nephrotoxic glutathione S-conjugates from tetrachloroethene; however, when compared with rats, the human capacity for the biosynthesis of N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine seems to be lower.

Hexachlorobuta-1,3-diene (HCBD) is a selective nephrotoxin and a potent nephrocarcinogen in rodents. Its toxicity and carcinogenicity is based on a multistep bioactivation pathway. Glutathione conjugation seems to be the only bioactivation pathway for HCBD leading to reactive intermediates, which are thought to be responsible for the observed nephrotoxic effects. Recent in vivo studies revealed a novel urinary metabolite in male, but not female, rats after administration of [14C]HCBD. This metabolite was identified as (E)-N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine-sulfoxide (N-Ac-PCBC-SO). The objective of this study was to elucidate the enzyme(s) involved in this particular oxidation and to find an explanation for the sex differences in the formation of N-Ac-PCBC-SO. Both cytochrome P450 and flavin-containing monooxygenases (FMO) may catalyze the oxidation of N-Ac-PCBC-SO. The use of various competitive and allosteric inhibitors of cytochrome P450 and FMO (i.e. metyrapone, N-benzylimidazole, thiobenzamide, CO, n-octylamine, and heat inactivation studies) showed that the sulfoxidation of (E)-N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)- L-cysteine is catalyzed by cytochrome P450 enzymes. In microsomes from male rats pretreated with pyridine, phenobarbital, and dexamethasone, an increase in the rates of sulfoxide formation was only seen in microsomes from dexamethasone- and phenobarbital-induced animals. Moreover, troleandomycin, a selective chemical inhibitor for enzymes of the cytochrome P4503A family, inhibited sulfoxide formation by > 80%. Correlation of sulfoxide formation with testosterone 6 beta-hydroxylation, a marker of cytochrome P4503A1/2 in the rat, underlined the finding that cytochrome P4503A is the predominant cytochrome P450 responsible for this particular oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)