Molecular mechanism of trichloroethylene-induced hepatotoxicity mediated by CYP2E1.
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.
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Japan.
Doni Hikmat
DH
Ramdhan
Michihiro
M
Kamijima
Naoyasu
N
Yamada
Yuki
Y
Ito
Yukie
Y
Yanagiba
Daichi
D
Nakamura
Ai
A
Okamura
Gaku
G
Ichihara
Toshifumi
T
Aoyama
Frank J
FJ
Gonzalez
Tamie
T
Nakajima
D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014241:Trichloroethylene / Q000633:toxicity*
D014241:Trichloroethylene; D019392:Cytochrome P-450 CYP2E1