Mechanism of chloroform-induced renal toxicity: Non-involvement of hepatic cytochrome P450-dependent metabolism

Journal Article · Fri Feb 15 04:00:00 EST 2008 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2007.10.014· OSTI ID:21077920

Cheng, Fang; Behr, Melissa; Fang, Xie; Shijun, Lu; Doret, Meghan; Hongxiu, Luo; Weizhu, Yang; Aldous, Kenneth; Xinxin, Ding ^[1]; Jun, Gu ^[1]

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1. Wadsworth Center, New York State Department of Health, Empire State Plaza, Box 509, Albany, NY 12201-0509 (United States)

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.

• OSTI ID: 21077920
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 227; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ALANINES
BLOOD
CHLOROFORM
ENZYMES
FIRST AID
GAS CHROMATOGRAPHY
IN VITRO
IN VIVO
KIDNEYS
KNOCK-OUT REACTIONS
LIVER
METABOLISM
MICE
NITROGEN
TOXICITY
UREA