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

Journal Article · Fri Jan 01 00:00:00 EST 1988 · Chem. Res. Toxicol.; (United States)

DOI:https://doi.org/10.1021/tx00001a007· OSTI ID:6065796

Veltman, J C; Dekant, W; Guengerich, F P; Anders, M W

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 then 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-450/sub PB-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 benzyl sulfides and cysteine S-conjugates.

• Research Organization: Univ. of Rochester, NY (USA)
• OSTI ID: 6065796
• Journal Information: Chem. Res. Toxicol.; (United States), Vol. 1:1
• Country of Publication: United States
• Language: English

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63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
BENZALDEHYDE
BIOLOGICAL EFFECTS
CARBON MONOXIDE
SULFIDES
METABOLISM
THIOLS
TOXICITY
CYSTEINE
CYTOCHROMES
ENZYME ACTIVITY
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RATS
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AMINO ACIDS
ANIMAL CELLS
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CARBON OXIDES
CARBOXYLIC ACIDS
CELL CONSTITUENTS
CHALCOGENIDES
ENZYMES
MAMMALS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANOIDS
OXIDES
OXIDOREDUCTASES
OXYGEN COMPOUNDS
OXYGENASES
PIGMENTS
PROTEINS
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560300* - Chemicals Metabolism & Toxicology