Ethanol-Drug Metabolic Interactions
Abstract
The present studies examined the effects of acute and chronic ethanol administration on the N-acetylation of arylamine containing drugs in two strains of mice which have been shown to be "rapid" and "slow" acetylators. In humans, differential toxicity of some drugs which undergo acetylation is dependent upon acetylator phenotype. Genetic slow acetylators are more prone to develop drug-induced systemic lupus erythematosis and polyneuropathy. Rapid acetylators are more prone to liver damage. The administration of ethanol to humans has been shown to increase the acetylation rate of sulfamethazine (SMZ) and procainamide (PA). Ethanol is metabolized to acetate, and theoretically could increase AcCoA levels, the acetate donor for the N-acetyltranferase (NAT) reaction. This could lead to increased acetylating capability by the liver and other tissues. To aid in the study of the human acetylation-ethanol interaction, the mouse models A/J and C57BL/6J (C57) strains, which have previously been shown to exhibit acetylation polymorphism, were studied utilizing a newly developed ethanol-containing liquid diet. Prior todetermining the regulation of acetylation by ethanol, the mice were first characterized for the inductive effects of the classical microsomal enzyme inducers (PB), 3-raethylcholanthrene (3-MC), and the polychlorinated biphenyl mixture, Aroclor 1254 (PCBs) to establish a basis of comparison with the ethanol induction studies. Following the characterization of the hepatic monooxygenases, a comparison was made of the inductive properties of ethanol in these mouse models. Finally the effects of acute and chronic ethanol administration on the acetylation rates of several test drugs were determined in the mouse model. The inducing properties of chronic ethanol ingestion on hepatic monooxygenases in Sprague-Dawley and Long-Evans rats, and A/J and C57 mice, were studied.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 13, 1984
- Accession Number
- AD1010704
Entities
People
- Robert G. Elves
Organizations
- Uniformed Services University of the Health Sciences