Pharmacological studies on the in vivo cataractogenicity of acetaminophen in mice and rabbits.
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 P-448) induction, and hepatocellular toxicity to cataractogenic susceptibility in inbred mice and rabbits. C57BL/6 or DBA/2 mice, which respectively are genetically responsive and nonresponsive to P-448 induction, were treated with acetaminophen, 300 to 1000 mg/kg intraperitoneally (ip), following pretreatment with the P-448 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: phenobarbital, 3-MC, or beta-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 biotransformation and toxicity.
Lubek
B M
BM
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Avaria
M
M
Basu
P K
PK
Wells
P G
PG
D000082:Acetaminophen / Q000633:toxicity* / Q000652:urine; D000818:Animals; D002386:Cataract / Q000139:chemically induced*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010634:Phenobarbital / Q000494:pharmacology; D011817:Rabbits
D000082:Acetaminophen; D008748:Methylcholanthrene; D010634:Phenobarbital