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- Title
Overexpression of CYP3A aggravates endotoxin-induced liver injury in hypophysectomized female rats.
- Authors
Takemura, Shigekazu; Minamiyama, Yukiko; Toyokuni, Shinya; Imaoka, Susumu; Hai, Seikan; Kubo, Shoji; Hirohashi, Kazuhiro; Funae, Yoshihiko; Okada, Shigeru
- Abstract
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.
- Subjects
RATS; ENDOTOXINS; LIVER injuries; HYPOPHYSECTOMY; REACTIVE oxygen species; CYTOCHROME P-450
- Publication
Hepatology Research, 2008, Vol 38, Issue 1, p70
- ISSN
1386-6346
- Publication type
Article
- DOI
10.1111/j.1872-034X.2007.00212.x