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 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.
Forkert
P G
PG
Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada.
Lee
R P
RP
Dowsley
T F
TF
Hong
J Y
JY
Ulreich
J B
JB
D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005260:Female; D008168:Lung / Q000187:drug effects* / Q000648:ultrastructure; D051379:Mice; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology*; D013997:Time Factors; D014752:Vinyl Chloride / Q000494:pharmacology*
D000498:Allyl Compounds; D013450:Sulfones; C068327:diallyl sulfone; D014752:Vinyl Chloride