Enhanced acetaminophen toxicity in rats with bilirubin glucuronyl transferase deficiency.
Glucuronidation is the major pathway for elimination of acetaminophen, diverting it from the toxifying pathway catalyzed by cytochromes P-450. A genetic deficiency in bilirubin UDP-glucuronyl transferase may predispose humans and animals to the toxicity of drugs that are extensively glucuronidated, if other glucuronyl transferase isoenzymes are concurrently deficient. Homozygous and heterozygous Gunn rats are, respectively, severely and moderately deficient in glucuronyl transferase. Acetaminophen (500 mg per kg) was administered intraperitoneally to homozygous and heterozygous Gunn rats and to Wistar controls. Hepatic and renal cellular damage was assessed by peak plasma concentrations of ALT and blood urea nitrogen, respectively. Homozygous and heterozygous Gunn rats showed, respectively, 115-fold and 9-fold higher ALT concentrations compared to Wistar controls. Blood urea nitrogen was elevated only in the homozygous Gunn rats (3-fold). Biotransformation of acetaminophen was measured by high-performance liquid chromatography. Acetaminophen glucuronidation was decreased by 72 and 35% (p less than 0.05), respectively, in the homozygous and heterozygous Gunn rats compared with Wistar controls. Production of acetaminophen glucuronide correlated negatively with ALT concentration (r = -0.89, p less than 0.001). Production of glutathione-derived metabolites, reflecting acetaminophen bioactivation, was 2 to 3-fold higher in the Gunn rats (p less than 0.05) and correlated with ALT concentrations (r = 0.90, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
de Morais
S M
SM
Faculty of Pharmacy, University of Toronto, Canada.
Wells
P G
PG
D000082:Acetaminophen / Q000097:blood / Q000378:metabolism* / Q000633:toxicity / Q000652:urine; D000818:Animals; D001711:Biotransformation; D005965:Glucuronates / Q000097:blood / Q000378:metabolism / Q000652:urine; D014453:Glucuronosyltransferase / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D011911:Rats, Gunn; D011919:Rats, Inbred Strains
D005965:Glucuronates; D000082:Acetaminophen; D014453:Glucuronosyltransferase