© 1988 Oxford University Press
research-article |
Pharmacological Studies on the in vivo Cataractogenicity of Acetaminophen in Mice and Rabbits1
*Faculty of Pharmacy, University of Toronto Toronto, Ontario, Canada
Department of Opthalmology, Faculty of Medicine, University of Toronto Toronto, Ontarto, Canada
Received January 21, 1987; accepted December 9, 1987
Pharmacological Studies on the in Vivo Cataractogenicity of Acetaminophen in Mice and Rabbits. LUBEK, B. M., AVARIA, M., BASU, P. K., AND WELLS, P. G. (1988). Fundam Appl Toxicol 10, 596–606. Acetaminophen can be enzymatically bioactivated, which may play a role in cataractogenesis. This study evaluated the relation of dose, sex, plasma drug concentration, cytochromes P-450 (P-450 and P448) induction, and hepatocellular toxicity to cataract-ogenic susceptibility in inbred mice and rabbits. C57BL/6 or DBA/2 mice, which respectively are genetically responsive and nonresponsive to P448 induction, were treated with acetaminophen, 300 to 1000 mg/kg intrapentoneally (ip), following pretreatment with the P448 inducer 3-methylcholanthrene (3-MC). Bilateral cataracts developed, independent of sex, in 83% of C57BL/6 mice within 4 hr of acetaminophen administration, compared with 7% of DBA/2 mice. A dose-response relation for cataractogenesis was evident in C57BL/6 mice using doses of 300 and 400 mg/kg, with the higher dose producing similar plasma acetaminophen concentrations but twofold higher glucuronide concentrations. Both strains had increased plasma concentrations of glutamic-pyruvic transaminase (GPT). New Zealand white or Chinchilla pigmented rabbits were treated with single or multiple doses of acetaminophen, 500 to 1500 mg/kg/day ip, following pretreatment with a cytochromes P-450 inducer: pheno-barbital, 3-MC, or ß3-naphthoflavone. Acetaminophen given chronically caused lenticular opacities within 1 week in 19 of 20 rabbits pretreated with P-450 inducers, regardless of pigmentation, but not in animals without prior P-450 induction. No opacities were observed after a single dose of acetaminophen, even with P-450 induction. There was no increase in plasma GPT in rabbits with any treatment. Over 85% of acetaminophen was recovered in urine as a glucuronide conjugate, and the rest as acetaminophen or conjugates with sulfate, cysteine, or N-acetylcysteine. Susceptibility to acetaminophen cataractogenesis can be genetically predetermined and may involve enzymatic bioactivation, possibly independent of hepatic biotrans-formation and toxicity.