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Enhanced acetaminophen toxicity in rats with bilirubin glucuronyl transferase deficiency
Author(s) -
de Morais Sonia M. F.,
Wells Peter G.
Publication year - 1989
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.1840100207
Subject(s) - transferase , toxicity , bilirubin , acetaminophen , medicine , chemistry , endocrinology , pharmacology , biochemistry , enzyme
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 < 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 < 0.001). Production of glutathione‐derived metabolites, reflecting acetaminophen bioactivation, was 2 to 3‐fold higher in the Gunn rats (p < 0.05) and correlated with ALT concentrations (r = 0.90, p < 0.001). The results indicate that heterozygous and homozygous deficiencies in glucuronyl transferase are, respectively, intermediate and major determinants of acetaminophen bioactivation and toxicity. Also, a genetic deficiency in bilirubin glucuronyl transferase in Gunn rats is associated with a deficiency in the glucuronidation of drug substrates.