title: Mechanism of chloroform-induced renal toxicity: non-involvement of hepatic cytochrome P450-dependent metabolism.
abstract: Chloroform causes hepatic and renal toxicity in a number of species. In vitro studies have indicated that chloroform can be metabolized by P450 enzymes in the kidney to nephrotoxic intermediate, although direct in vivo evidence for the role of renal P450 in the nephrotoxicity has not been reported. This study was to determine whether chloroform renal toxicity persists in a mouse model with a liver-specific deletion of the P450 reductase (Cpr) gene (liver-Cpr-null). Chloroform-induced renal toxicity and chloroform tissue levels were compared between the liver-Cpr-null and wild-type mice at 24 h following differing doses of chloroform. At a chloroform dose of 150 mg/kg, the levels of blood urea nitrogen (BUN) were five times higher in the exposed group than in the vehicle-treated one for the liver-Cpr-null mice, but they were only slightly higher in the exposed group than in the vehicle-treated group for the wild-type mice. Severe lesions were found in the kidney of the liver-Cpr-null mice, while only mild lesions were found in the wild-type mice. At a chloroform dose of 300 mg/kg, severe kidney lesions were observed in both strains, yet the BUN levels were still higher in the liver-Cpr-null than in the wild-type mice. Higher chloroform levels were found in the tissues of the liver-Cpr-null mice. These findings indicated that loss of hepatic P450-dependent chloroform metabolism does not protect against chloroform-induced renal toxicity, suggesting that renal P450 enzymes play an essential role in chloroform renal toxicity.
authors.affiliation: Wadsworth Center, New York State Department of Health, Albany, NY 12201-0509, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Fang
authors.forename: Melissa
authors.initials: M
authors.lastname: Behr
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.forename: Shijun
authors.initials: S
authors.lastname: Lu
authors.forename: Meghan
authors.initials: M
authors.lastname: Doret
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Luo
authors.forename: Weizhu
authors.initials: W
authors.lastname: Yang
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldous
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ding
authors.forename: Jun
authors.initials: J
authors.lastname: Gu
mesh_terms: D000818:Animals; D001682:Biological Availability; D002725:Chloroform / Q000493:pharmacokinetics / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D002725:Chloroform; D003577:Cytochrome P-450 Enzyme System