A unique pharmacogenetic expression of the N-acetylation polymorphism in the inbred hamster.
Liver N-acetyltransferase (NAT) preparations (105,000 x g cytosol) were obtained from both sexes of 26 strains of inbred hamsters. Liver NAT activity levels were determined for six arylamine substrates; isoniazid, p-aminobenzoic acid (PABA), p-aminosalicylic acid (PAS), sulfamethazine (SMZ), procainamide and 2-aminofluorene. The N-acetylation of isoniazid, SMZ, procainamide and 2-aminofluorene exhibited a monomorphic expression in the hamster as the genetic variation in NAT activity levels between hamster strains was only about 2-fold for each substrate. In contrast, the N-acetylation of PABA and PAS showed a polymorphic expression in the hamster. Two inbred hamster lines (Bio 1.5 and Bio 82.73) had over 400-fold lower PABA NAT and over 20-fold lower PAS NAT activity levels than did the other inbred strains. In addition, the genetically determined N-acetylation differences between the rapid and slow acetylator hamster strains were also demonstrated in vivo for PABA but not for SMZ. Comparison of Michaelis-Menten kinetic constants of PABA NAT activity in a rapid and slow acetylator strain showed a 20-fold lower Km in the rapid acetylator strain suggesting an intrinsic structural difference in rapid and slow acetylator hamster liver NAT. Thus, the pharmacogenetic expression of the N-acetylation polymorphism is quite unique in the inbred hamster, in that PABA and PAS are genetically polymorphic substrates, whereas isoniazid, SMZ, procainamide and 2-aminofluorene are monomorphic, in direct contrast to man and rabbit.
D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006224:Cricetinae / Q000378:metabolism*; D005260:Female; D007700:Kinetics; D008297:Male; D008647:Mesocricetus / Q000235:genetics / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011110:Polymorphism, Genetic
D004364:Pharmaceutical Preparations; D000123:Acetyltransferases