Abstract
A survey among 20 inbred mouse strains revealed large variation (up to approximately 20-fold) for the N-acetylation of p-aminobenzoic acid by blood N-acetyltransferase and for the aromatic amine carcinogen benzidine by both liver and blood N-acetyltransferase. Of 20 strains surveyed, three are classified as slow acetylators (A/J, AHe/J, and X/Gf) and 17 are classified as rapid acetylators (AuSsJ, Castaneous, ST/bJ, C57BL/6J, Molossinus, SF, SWR/J, 129/SV, RF/J, RIII/2J, IsCam, SJL/J, Balb/cJ, C3H/HeJ, CBA/J, AKR/J, and DBA/J). The rapid acetylator strains possessed approximately 10 times greater liver benzidine N-acetyltransferase specific activity than the slow acetylator strains. Intercross and backcross matings of A/J and C57BL/6J mice indicate that a single gene with two major alleles is responsible for differences in N-acetyltransferase activity in blood for p-aminobenzoic acid or the alternate aromatic amine carcinogen aminofluorene, and in liver for aminofluorene. Analysis of 11 recombinant inbred strains derived from matings of A/J with C57BL/6J mice support this conclusion and demonstrate the existence of minor modifying genes that segregate independently of the major N-acetyltransferase gene.
Highlights
The rapidacetylatorstrains possessed -10 times greater liver benzidine N-acetyltransferase specifaicctivity than the slow acetylator strains
Backcross matingsof A/J and C57BL/6J mice indicate In human populations, the acetylation polymorphism plays that asingle gene withtwo major alleles is responsible an important role in determining the variability seen in the for differencesin N-acetyltransferase activityin blood incidence of toxic responses to certain arylamine drugs such forp-aminobenzoicacidorthealternatearomatic as INH, procainamide, and hydralazine (Drayer and Reidenamine carcinogen aminofluorene, andin liver for ami- berg, 1977)R. ecent studies have indicated that theacetylation nofluorene
A/J mice had a higher incidence of spontaneous antinuclear antibodies than C57BL/6Jmice; and that these antibodies could be induced by oral procainamide (Tannen and Weber, In man and rabbit, the rate of N-acetylation of arylamine drugs such as sulfamethazine, isoniazid, hydralazine, and procainamide is subject to a genetic polymorphism, attributable to a difference in the amount of N-acetyltransferase activity (EC 2.3.1.5) in liver (Weber, 1973; Weber et al, 1976; DuSouich and E d, 1976;Glowinski et al 1980)
Summary
In human and rabbit populations, certain aromatic amine carcinogenssuch as AF, BZ and 2-naphthylamine are acetylated by the same polymorphic N-acetyltransferase that is responsible forthe acetylation of arylamine drugs (Glowinskiet al., 1978).This hasled to thespeculation that rapid and slow of Pharmacology, Medical Science I 6322, University of Michigan, acetylator populations may differ insusceptibility to aromatic. Onepreliminary report suggests that slow acetylators may be at greater risk of urinary bladder tumors from. Genetics of AromAamtiNcin-Aecetylation in Inbred Mice aromatic amine carcinogen exposure ( L et al.~, 197~9), further studies in appropriate human are necessary to establish this. In an attempt todevelop new animal models forthe N-acetylation polymorphism and thereby possibly assess its effect on tumor susceptibility,these studies were undertaken to analyze the genetic basis of strain differences in aromatic amine carcinogen N-acetylation in inbred mice. ~ i ~ ~ ~ - w~er~e wbe ad blysdecapitation, livers removed and homogenized by hand in 4 volumes of 50 m~ potassium phosphate buffer, 1 mM dithiothreitol, pH 7.4, in a ground glass homogenizer. Homogenates were centrifuged a t 1 0 , m X g for 20 min, and the resulting at 105~000x g for h
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