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Identification of genetically homozygous rapid and slow acetylators of drugs and environmental carcinogens among established inbred rabbit strains

Journal Article · · J. Pharmacol. Exp. Ther.; (United States)
OSTI ID:6563219
; ; ;
Liver and gut mucosa N-acetyltransferase (NAT) cytosol (105,000 x g) was prepared from selected lines of New Zealand White rapid and slow acetylator rabbits bred and housed at the University of Michigan, and from inbred and partially inbred rabbits obtained from The Jackson Laboratory. Liver NAT activity was determined with p-aminobenzoic acid, p-aminosalicylic acid, procainamide, sulfamethazine, isoniazid and 2-aminofluorene as substrates. Gut mucosal NAT activity was determined with 2-aminofluorene. A gene dose-response relationship was observed for both liver NAT and gut mucosa NAT with all substrates tested. Highest levels were always observed in homozygous rapid acetylator inbred strains (B/J, III/J, IIIC/J, III/DwJ, IIIEP/J and IIIVO/J), lower levels in obligate heterozygous rapid acetylator rabbits and lowest levels in homozygous slow acetylator inbred (ACEP/J, III/cdJ, IIIVO/ahJ, and IIIVO/vptJ) and outbred rabbits. The differences in magnitude of liver NAT activity level between acetylator genotypes was dependent on the substrate employed, progressively increasing in the following order: p-aminobenzoic acid, p-aminosalicyclic acid, procainamide, sulfamethazine, isoniazid, 2-aminofluorene. The determination of kinetic constants for liver p-aminosalicyclic acid NAT activity indicated a 2-fold difference in apparent Vmax between rapid acetylator genotypes and a 30-fold difference between rapid and slow acetylator phenotypes. In addition, the apparent Km for p-aminosalicyclic acid was significantly lower in the slow acetylators than in the rapid acetylators.
Research Organization:
Department of Pharmacology, The University of Michigan School of Medicine, Ann Arbor
OSTI ID:
6563219
Journal Information:
J. Pharmacol. Exp. Ther.; (United States), Journal Name: J. Pharmacol. Exp. Ther.; (United States) Vol. 223:1; ISSN JPETA
Country of Publication:
United States
Language:
English

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Related Subjects

560305* -- Chemicals Metabolism & Toxicology-- Vertebrates-- (-1987)
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ACETYLATION
ACYLATION
AMINO ACIDS
ANIMALS
ANTI-INFECTIVE AGENTS
ANTIMICROBIAL AGENTS
BIOCHEMICAL REACTION KINETICS
BODY
CARBOXYLIC ACIDS
CARCINOGENS
CHEMICAL REACTIONS
DIGESTIVE SYSTEM
DRUGS
ENZYMES
GASTROINTESTINAL TRACT
GLANDS
HYDRAZIDES
INTESTINES
ISONIAZID
KINETICS
LIVER
MAMMALS
METABOLISM
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PABA
PAS
RABBITS
REACTION KINETICS
TRANSFERASES
VERTEBRATES