Enhanced acetaminophen toxicity in rats with bilirubin glucuronyl transferase deficiency
Article first published online: 6 DEC 2005
Copyright © 1989 American Association for the Study of Liver Diseases
Volume 10, Issue 2, pages 163–167, August 1989
How to Cite
de Morais, S. M. F. and Wells, P. G. (1989), Enhanced acetaminophen toxicity in rats with bilirubin glucuronyl transferase deficiency. Hepatology, 10: 163–167. doi: 10.1002/hep.1840100207
- Issue published online: 6 DEC 2005
- Article first published online: 6 DEC 2005
- Manuscript Accepted: 26 JAN 1989
- Manuscript Received: 6 SEP 1988
- Medical Research Council of Canada
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico
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.