Protection from 1,1-dichloroethylene-induced Clara cell injury by diallyl sulfone, a derivative of garlic

P. G. Forkert, R. P. Lee, T. F. Dowsley, J. Y. Hong, J. B. Ulreich

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22 Scopus citations

Abstract

Bronchiolar Clara cell damage ensues after treatment of mice with 1,1- dichloroethylene (DCE). The cytotoxicity is mediated by CYP2E1, a cytochrome P450 isozyme that is highly localized in the Clara cells. Bioactivation of DCE produces the primary metabolites 2,2-dichloroacetaldehyde, which hydrolyzes to the acetal, and DCE epoxide, which reacts with glutathione to form the conjugates 2-(S-glutathionyl) acetyl glutathione [B] and 2-S- glutathionyl acetate [C]. In this study, we investigated the potential of diallyl sulfone (DASO2) to inhibit CYP2E1, to suppress the bioactivation of DCE to reactive intermediates and to abrogate DCE-induced Clara cell cytotoxicity. Our results showed that treatment of mice with DASO2 (100 mg/kg p.o.) produced decreases in CYP2E1-dependent p-nitrophenol hydroxylation that were apparent at 1 h. Enzyme activity plummeted to about 20% of the control by 2 h and remained at this low level from 3 to 8 h. Recovery of activity was evident at 16 h and returned to the control level by 24 h. Immunoreactivity of the CYP2E1 protein was decreased in immunoblots of lung microsomes from DASO2-treated mice. Treatment with DASO2 did not cause any structural alterations in lung tissue; in contrast, treatment with DCE (75 mg/kg) produced Clara cell damage. This lesion was not manifested in mice treated with DASO2 in conjunction with DCE. The lack of cytotoxicity observed in vivo correlated with a reduction of about 45% in the levels of both the acetal and the DCE epoxide-derived conjugates [B] and [C] in vitro. These results demonstrated that DASO2 significantly inhibited the CYP2E1 enzyme, decreased the production of DCE metabolites and protected Clara cells from DCE-induced cytotoxicity.

Original languageEnglish (US)
Pages (from-to)1665-1671
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume277
Issue number3
StatePublished - Jun 1 1996

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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