Role of nuclear receptor CAR in carbon tetrachloride-induced hepatotoxicity.
OBJECTIVE
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.


CONCLUSIONS
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.
Yamazaki
Yuichi
Y
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi 371-8511, Japan.
Kakizaki
Satoru
S
Horiguchi
Norio
N
Takagi
Hitoshi
H
Mori
Masatomo
M
Negishi
Masahiko
M
D000732:Androstanols / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002251:Carbon Tetrachloride / Q000633:toxicity*; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D010634:Phenobarbital / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011991:Receptors, Virus / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D000732:Androstanols; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D018076:DNA, Complementary; D012333:RNA, Messenger; D011991:Receptors, Virus; C000658:androstan-3-ol; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D005978:Glutathione; D010634:Phenobarbital