Cytochrome P450 (
CYP) 2E1 was suggested to be the major
enzyme involved in
trichloroethylene (TRI) metabolism and TRI-induced hepatotoxicity, although the latter molecular mechanism is not fully understood. The involvement of
CYP2E1 in TRI-induced hepatotoxicity and its underlying molecular mechanism were studied by comparing hepatotoxicity in
cyp2e1+/+ and
cyp2e1-/- mice. The mice were exposed by inhalation to 0 (control), 1000, or 2000 ppm of TRI for 8 h a day, for 7 days, and TRI-hepatotoxicity was assessed by measuring plasma
alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) activities and histopathology. Urinary metabolites of
trichloroethanol and
trichloroacetic acid (TCA) were considerably greater in
cyp2e1+/+ compared to
cyp2e1-/- mice, suggesting that
CYP2E1 is the major P450 involved in the formation of these metabolites. Consistent with elevated plasma ALT and AST activities,
cyp2e1+/+ mice in the 2000 ppm group showed histopathological
inflammation. TRI significantly upregulated
PPARalpha, which might function to inhibit NFkappaB p50 and p65 signalling. In addition, TRI-induced NFkappaB p52
mRNA, and significantly positive correlation between NFkappaB p52
mRNA expression and plasma ALT activity levels were observed, suggesting the involvement of p52 in liver
inflammation. Taken together, the current study directly demonstrates that
CYP2E1 was the major P450 involved in the first step of the TRI metabolism, and the metabolites produced may have two opposing roles: one inducing hepatotoxicity and the other protecting against the toxicity. Intermediate metabolite(s) from TRI to
chloral hydrate produced by CYP2E1-mediated oxidation may be involved in the former, and TCA in the latter.