J Pharmacol Exp Ther. 1996 Jun;277(3):1665-71.  

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

Forkert PG, Lee RP, Dowsley TF, Hong JY, Ulreich JB.

Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario,
Canada.

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.

PMID: 8667236 [PubMed - indexed for MEDLINE]