title: Overexpression of CYP3A aggravates endotoxin-induced liver injury in hypophysectomized female rats.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Overexpression of CYP3A aggravated LPS-induced liver injury in rats, apparently through the formation of reactive oxygen species.
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Takemura
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Minamiyama
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
authors.forename: Susumu
authors.initials: S
authors.lastname: Imaoka
authors.forename: Seikan
authors.initials: S
authors.lastname: Hai
authors.forename: Shoji
authors.initials: S
authors.lastname: Kubo
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hirohashi
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Funae
authors.forename: Shigeru
authors.initials: S
authors.lastname: Okada