ARYLAMINE N-ACETYLTRANSFERASES - GENETIC- POLYMORPHISM AND SUSCEPTIBILITY TO XENOBIOTICS

Interindividual variability in the metabolism of xenobiotics, includin g drugs anti environmental pollutants, is in part due to genetic polym orphisms of enzymes involved in biotransformation., Pharmacogenetics f ocuses on their study. In man, two arylamine N-acetyltransferases, NAT 1 and NAT2, are among the best documented examples of polymorphic biot ransformation enzymes. Their genes, NAT1 and NAT2, both located on chr omosome 8p21.3-23.1, have very similar sequences and may: be the produ cts of an ancestral gene duplication, NAT1 is expressed in various tis sues; whereas NAT2 is mostly expressed in liver and intestine and is t he best-studied polymorphic locus, Enzyme variants produced by this ge ne polymorphism have functional properties that dictate the ''slow'' o r ''rapid'' acetylator phenotypes. The implications of this polymorphi sm for both therapeutics and cancerology have been extensively studied . The ''slow acetylator'' phenotype is often associated with adverse d rug reactions: Particular genetic combinations of NATs and other biotr ansformations enzymes have also been associated with susceptibility to some non iatrogenic pathologies including cancers. The mechanisms of detoxification and/or activation of xenobiotics involve both inactivat ing conjugation and synthesis of reactive ions capable of binding to c ellular macromolecules. The study of NAT structure function relationsh ips may contribute to our understanding of these mechanisms.