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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 · · Chem. Res. Toxicol.; (United States)
DOI:https://doi.org/10.1021/tx00001a007· OSTI ID:6065796
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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), Journal Name: Chem. Res. Toxicol.; (United States) Vol. 1:1; ISSN CRTOE
Country of Publication:
United States
Language:
English

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Related Subjects

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