Acetylation pharmacogenetics: profiles of arylamine pharmacology and toxicology in a genetic mouse model.

Acetylation, a major pathway for conjugation and excretion of foreign compounds, is a common route of arylamine biotransformation (Williams, 1959) and an important factor in the expression of mutagenic, carcinogenic and more acute effects of these substances (King & Weber, 1981). An hereditary polymorphism in acetylation, due to genetic variation in the activity of liver and gut mucosal NAT activity, is an interesting feature of this reaction which is well known both in man and rabbit enabling individuals in each of these species to be classified as 'rapid' and 'slow' acetylators of many arylamines and hydrazines in the environment (Weber & Glowinski, 1980). Human genetic epidemiological studies have shown that slow acetylators are predisposed to toxicity from arylamine and hydrazine drugs (Weber & Hein, 1984) and to urinary bladder cancer resulting from arylamine carcinogens (Cartwright et al., 1982). These studies are essential but in some instances they have led to controversy about the relationship of acetylator status to these effects, perhaps because they are based on epidemiological data from selected patient groups rather than on more precise experimental studies in animals (Weber et al., 1983). Thus we have concentrated on developing and characterizing experimental models for the human acetylation polymorphism as tools for elucidation of pharmacogenetic factors which can modify toxicity or reveal other peculiar responses to arylamine drugs and carcinogens. Recently we have identified hereditary acetylation polymorphisms in the mouse (Glowinski & Weber, 1982a, b and hamster (Hein et al., 1982). It was apparent from a survey of some 20 inbred mouse strains that most strains were rapid acetylators as typified by C57BL/6J (B6) mice, but a few strains (A/J, AHe/J, XG/f) were slow acetylators of certain carcinogens (Glowinski et al., 1982~). Genetic analysis of the mouse trait in B6 and A mice, which were selected for further study, indicated that the NAT activity in these mice is primarily controlled by a single gene wiht two major alleles. B6 mice have approximately ten times more NAT activity for benzidine, and for the alternative substrate, AF, than A/J (A) mice. Moreover, the levels of liver NAT activity were similar to levels that have been reported for human liver NAT in rapid and slow acetylators (Glowinski et al., 1978). An apparent K,,, difference of some 20-fold between A and B6 mouse liver AF NAT suggests that the inter-strain difference in B6 and A N-acetylating activity is probably accounted for by a structural difference in the NAT gene product (Glowinski & Weber, 1982b). We are currently investigating the pharmacologic and toxicdogic profiles of AF and MDA in relation to acetylator status in further characterizing the genetic mouse model. We have investigated the dose-response characteristics and pharmacokinetics of AF both in intact A, B6, B6AF1, and A.B6-NAT' animals and in hepatocytes isolated from A and B6 animals, and have obtained preliminary results on AFinduced DNA damage in A and B6 hepatocytes. Relatively little is known about the biological effects of MDA even though in man acute exposure produces a distinct picture of