title: Cytotoxicity and bioactivation mechanism of benzyl 2-chloro-1,1,2-trifluoroethyl sulfide and benzyl 1,2,3,4,4-pentachlorobuta-1,3-dienyl sulfide.
abstract: The metabolism and cytotoxicity of benzyl 1,2,3,4,4-pentachlorobuta-1,3-dienyl sulfide (1) and benzyl 2-chloro-1,1,2-trifluoroethyl sulfide (2) were studied as an alternative test of the hypothesis that the toxicity of the cysteine S-conjugates S-(pentachlorobutadienyl)-L-cysteine and S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine is associated with their metabolism to unstable thiols; the expectation was that the benzyl sulfides 1 and 2 would undergo cytochrome P-450 dependent benzylic hydroxylation and that the intermediate hemimercaptals would eliminate unstable, cytotoxic thiols. This expectation was realized: 1 and 2 were cytotoxic in isolated rat hepatocytes. The cytotoxicity of 1 was greater in hepatocytes from phenobarbital-treated rats compared with control rats and in male than in female rats and was inhibited by carbon monoxide and 2-(N,N-diethylamino)ethyl 2,2-diphenylvalerate HCl (SKF 525-A). Benzyl sulfides 1 and 2 were metabolized to benzaldehyde by rat hepatic microsomal fractions and by a purified, reconstituted cytochrome P-450PB-B system. Benzaldehyde was not cytotoxic. These results provide support for the hypothesis that benzyl sulfides 1 and 2 and the corresponding cysteine S-conjugates yield unstable thiols, which may give rise to acylating agents or to stable, but toxic, terminal products that are responsible for the cytotoxic effects of the benzyl sulfides and cysteine S-conjugates.
authors.affiliation: Department of Pharmacology, University of Rochester, New York 14620.
authors.forename: J C
authors.initials: JC
authors.lastname: Veltman
authors.forename: W
authors.initials: W
authors.lastname: Dekant
authors.forename: F P
authors.initials: FP
authors.lastname: Guengerich
authors.forename: M W
authors.initials: MW
authors.lastname: Anders
mesh_terms: D000818:Animals; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation; D002070:Butadienes / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D008099:Liver / Q000166:cytology* / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D012727:Sex Characteristics; D013440:Sulfides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001593:Benzyl Compounds; D002070:Butadienes; D013440:Sulfides; C072635:benzylpentachlorobuta-1,3-dienyl sulfide; D002248:Carbon Monoxide; C072634:benzyl-2-chloro-1,1,2-trifluoroethyl sulfide; D011335:Proadifen