PROTECTION FROM 1,1-DICHLOROETHYLENE-INDUCED CLARA CELL INJURY BY DIALLYL SULFONE, A DERIVATIVE OF GARLIC

Bronchiolar Clara cell damage ensues after treatment of mice with 1,1- dichloroethylene (DCE). The cytotoxicity is mediated by CYP2E1, a cyto chrome P450 isozyme that is highly localized in the Clara cells. Bioac tivation of DCE produces the primary metabolites 2,2-dichloroacetaldeh yde, which hydrolyzes to the acetal, and DCE epoxide, which reacts wit h glutathione to form the conjugates 2-(S-glutathionyl) acetyl glutath ione [B] and 2-S-glutathionyl acetate [C]. In this study, we investiga ted the potential of diallyl sulfone (DASO(2)) to inhibit CYP2E1, to s uppress the bioactivation of DCE to reactive intermediates and to abro gate DCE-induced Clara cell cytotoxicity. Our results showed that trea tment of mice with DASO(2) (100 mg/kg p.o.) produced decreases in CYP2 E1-dependent p-nitrophenol hydroxylation that were apparent at 1 h. En zyme activity plummeted to about 20% of the control by 2 h and remaine d 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 t he CYP2E1 protein was decreased in immunoblots of lung microsomes from DASO(2)-treated mice. Treatment with DASO(2) did not cause any struct ural alterations in lung tissue; in contrast, treatment with DCE (75 m g/kg) produced Clara cell damage. This lesion was not manifested in mi ce treated with DASO(2) in conjunction with DCE. The lack of cytotoxic ity observed in vivo correlated with a reduction of about 45% in the l evels of both the acetal and the DCE epoxide-derived conjugates [B] an d [C] in vitro. These results demonstrated that DASO(2) significantly inhibited the CYP2E1 enzyme, decreased the production of DCE metabolit es and protected Clara cells from DCE-induced cytotoxicity.