Comparison of 6 rabbit liver cytochrome p 450 isozymes in formation of a reactive metabolite of acetaminophen

Morgan, E.T.; Koop, D.R.; Coon, M.J.

Biochemical and Biophysical Research Communications 112(1): 8-13


ISSN/ISBN: 0006-291X
Accession: 005004541

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An ethanol-inducible form of rabbit liver microsomal cytochrome P-450, designated isozyme 3a was isolated. Since the hepatotoxicity of acetaminophen is increased in ethanol-treated animals and the human alcoholic, the activity of the 6 available P-450 isozymes in the activation of the drug to give an intermediate which forms a conjugate with reduced glutathione was determined. Isozymes 3a, 4 and 6, all of which are present in significant amounts in the liver microsomes from rabbits chronically administered ethanol, exhibited the highest activities in the reconstituted enzyme system, whereas isozymes 3b and 3c were 10- to 20-fold less effective, and phenobarbital-inducible isozyme 2 was essentially inactive, even in the presence of cytochrome b5. Evidently induction by ethanol of P-450 isozyme 3a (or a homologous enzyme in other species) may contribute to the toxicity of acetaminophen but that other cytochromes also play a significant role.