Yamazaki Yuichi, Kakizaki Satoru, Horiguchi Norio, Takagi Hitoshi, Mori Masatomo, Negishi Masahiko
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi 371-8511, Japan.
World J Gastroenterol. 2005 Oct 14;11(38):5966-72. doi: 10.3748/wjg.v11.i38.5966.
To investigate the precise roles of CAR in CCl(4)-induced acute hepatotoxicity.
To prepare an acute liver injury model, CCl(4) was intraperitoneally injected in CAR+/+ and CAR-/- mice.
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.
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.
研究组成型雄烷受体（CAR）在四氯化碳（CCl₄）诱导的急性肝毒性中的确切作用。
为制备急性肝损伤模型，对CAR+/+和CAR-/-小鼠腹腔注射CCl₄。
与未使用苯巴比妥（PB）的CAR+/+小鼠相比，CAR-/-小鼠血清丙氨酸氨基转移酶升高及中央小叶坏死范围略有抑制。给予CAR诱导剂PB后发现，与CAR+/+小鼠相比，CAR-/-小鼠中CCl₄诱导的肝毒性受到部分抑制。另一方面，反式激动剂配体雄甾醇抑制了CAR+/+小鼠的肝毒性，但对CAR-/-小鼠无效。因此，CAR激活导致CCl₄肝毒性，而CAR抑制导致对CCl₄诱导的肝毒性有部分保护作用。CAR+/+和CAR-/-小鼠之间，CCl₄的主要代谢酶CYP2E1的表达没有差异。然而，PB可诱导CAR+/+小鼠中其他CCl₄代谢酶如CYP2B10和3A11的表达，但对CAR-/-小鼠无此作用。虽然CCl₄诱导急性肝损伤的主要途径由CYP2E1介导，但在存在激活剂或抑制剂的情况下，CAR通过诱导CYP2B10和3A11来调节该途径。
核受体CAR在存在激活剂的情况下，通过诱导CCl₄代谢酶来调节CCl₄诱导的肝损伤。我们的结果表明，即使与核受体相互作用的药物本身无肝毒性，如PB，它们也可能在药物性肝损伤或药物相互作用中起关键作用。
