A UNIQUE PHARMACOGENETIC EXPRESSION OF THE N-ACETYLATION POLYMORPHISM IN THE INBRED HAMSTER

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  • 1 January 1982
    • journal article
    • research article
    • Vol. 220  (1) , 8-15
Abstract
Liver N-acetyltransferase (NAT) preparations (105,000 .times. g cytosol) were obtained from both sexes of 26 strains of inbred hamsters. Liver NAT activity levels were determined for 6 arylamine substrates; isoniazid, p-aminobenzoic acid (PABA), p-aminosalicyclic 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. 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. 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. The pharmacogenetic expression of the N-acetylation polymorphism was evidently 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.