Premium
Overexpression of CYP3A aggravates endotoxin‐induced liver injury in hypophysectomized female rats
Author(s) -
Takemura Shigekazu,
Minamiyama Yukiko,
Toyokuni Shinya,
Imaoka Susumu,
Hai Seikan,
Kubo Shoji,
Hirohashi Kazuhiro,
Funae Yoshihiko,
Okada Shigeru
Publication year - 2008
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/j.1872-034x.2007.00212.x
Subject(s) - medicine , endocrinology , lipopolysaccharide , cyp3a , liver injury , ccl4 , cytochrome p450 , hypophysectomy , ketoconazole , phenobarbital , chemistry , biology , carbon tetrachloride , hormone , metabolism , organic chemistry , antifungal , microbiology and biotechnology
Aim: CYP3A2 is a male‐specific isoform of cytochrome P450 enzyme which is expressed abundantly in male rats but not in intact female rats. Having previously reported that hepatic CYP3A2 promotes lipopolysaccharide (LPS)‐induced liver injury in male rats, we further examined the impact of CYP3A on LPS‐induced liver injury by comparing intact and hypophysectomized female rats. In hypophysectomized female rats, phenobarbital (PB), a cytochrome P450 inducer, markedly increased the hepatic content and activity of CYP3A1/2, but did not do so in intact rats. CYP2B1 increased to similar levels in PB‐treated hypophysectomized and intact rats. Methods: Rats were administered 10 mg/kg LPS intravenously and some were given PB for three days before LPS injection. Liver injury was analyzed 8 h after LPS injection. Results: PB–LPS increased plasma alanine aminotransferase significantly more in hypophysectomized female rats than in intact female rats. Ketoconazole, a CYP3A inhibitor, inhibited the increase of liver injury. Hepatic 8‐hydroxydeoxyguanosine in nuclei and 4‐hydroxy‐2‐nonenal‐modified proteins, measured to evaluate oxidative stress by LPS treatment, increased markedly more in PB‐treated, hypophysectomized female rats, than in intact female rats. Conclusion: Overexpression of CYP3A aggravated LPS‐induced liver injury in rats, apparently through the formation of reactive oxygen species.