Role of nuclear receptor CAR in carbon tetrachloride-induced hepatotoxicity

AIM: To investigate the precise roles of CAR in CCl4-induced acute hepatotoxicity.METHODS: To prepare an acute liver injury model, CCl4 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 CCl4-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 CCl4 hepatotoxicity while CAR inhibition resulted in partial protection against CCl4-induced hepatotoxicity.There were no differences in the expression of CYP2E1, the main metabolizing enzyme for CCl4, between CAR+/+ and CAR-/- mice. However, the expression of other CCl4-metabolizing enzymes, such as CYP2B10 and 3A11, was induced by PB in CAR+/+ but not in CAR-/- mice. Although the main pathway of CCl4-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 CCl4-induced liver injury via induction of CCl4-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 drugdrug interaction even though such drugs themselves are not hepatotoxic.

AIM： To investigate the precise roles of CAR in CCI4- induced acute hepatotoxicity. METHODS： To prepare an acute liver injury model, CCI4 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 CCl4-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 CCl4 hepatotoxicity while CAR inhibition resulted in partial protection against CCl4-induced hepatotoxicity.There were no differences in the expression of CYP2E1, the main metabolizing enzyme for CCl4, between CAR＋/＋ and CAR./. mice. However, the expression of other CCI4-metabolizing enzymes, such as CYP2B10 and 3All, was induced by PB in CAR＋/＋ but not in CAR-/- mice. Although the main pathway of CCl4-induced acute liver injury is mediated by CYP2E1, CAR modulates its pathway via induction of CYP2B10 and 3All in the presence of activator or inhibitor. CONCLUSION： The nuclear receptor CAR modulates CCl4- induced liver injury via induction of CCl4-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.