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Yamazaki Y, Kakizaki S, Horiguchi N, Takagi H, Mori M, Negishi M: Role of nuclear receptor CAR in carbon tetrachloride-induced hepatotoxicity. World J Gastroenterol. 2005 Oct 14;11(38):5966-72.
AIM: To investigate the precise roles of CAR in CCl (4)-induced acute hepatotoxicity. METHODS:To prepare an acute liver injury model, CCl (4) was intraperitoneally injected in CAR+/+ and CAR-/- mice. RESULTS: Elevation of serum alanine aminotransferase and extension of centrilobular necrosis were slightly inhibited in CAR-/- mice compared to CAR+/+ mice without PB. Administration of a CAR inducer, PB, revealed that CCl (4)-induced liver toxicity was partially inhibited in CAR-/- mice compared with CAR+/+ mice. On the other hand, androstanol, an inverse agonist ligand, inhibited hepatotoxicity in CAR+/+ but not in CAR-/- mice. Thus, CAR activation caused CCl (4) hepatotoxicity while CAR inhibition resulted in partial protection against CCl (4)-induced hepatotoxicity. There were no differences in the expression of CYP2E1, the main metabolizing enzyme for CCl (4), between CAR+/+ and CAR-/- mice. However, the expression of other CCl (4)-metabolizing enzymes, such as CYP2B10 and 3A11, was induced by PB in CAR+/+ but not in CAR-/- mice. Although the main pathway of CCl (4)-induced acute liver injury is mediated by CYP2E1, CAR modulates its pathway via induction of CYP2B10 and 3A11 in the presence of activator or inhibitor. CONCLUSION: The nuclear receptor CAR modulates CCl (4)-induced liver injury via induction of CCl (4)-metabolizing enzymes in the presence of an activator. Our results suggest that drugs interacting with nuclear receptors such as PB might play critical roles in drug-induced liver injury or drug-drug interaction even though such drugs themselves are not hepatotoxic. |
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