METABOLIC-ACTIVATION OF AROMATIC AND HETEROCYCLIC N-HYDROXYARYLAMINESBY WILD-TYPE AND MUTANT RECOMBINANT HUMAN NAT1 AND NAT2 ACETYLTRANSFERASES

Recombinant human NAT1 and polymorphic NAT2 wild-type and mutant N-ace tyltransferasee (encoded by NAT2 alleles with mutations at 282/857, 19 1, 282/590, 341/803, 341/481/803, and 341/481) were expressed in Esche richia coli strains XA90 and/or JM105, and tested for their capacity t o catalyze the metabolic activation (via O-acetylation) of the N-hydro xy (N-OH) derivatives of Zaminofluorene (AF), and the heterocyclic ary lamine mutagens 2-amino-3-methylimidazo [4,5-f]quinoline (IQ), 2-amino -3,4-dimethyl-imidazo [4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl -6-phenylimidazo [4,5-b]pyridine (PhLP). Both NAT1 and NAT2 (including all mutant human NAT2s tested) catalyzed the metabolic activation of each of the N-hydroxyarylamines to products that bound to DNA. Metabol ic activation of N-OH-AF was greater than that of the heterocyclic N-h ydroxyarylamines. The relative capacity of NAT1 versus NAT2 to catalyz e activation varied with N-hydroxyarylamine substrate. N-OH-MeIQx and N-OH-PhIP exhibited a relative specificity for NAT2. These results pro vide mechanistic support for a role of the genetic acetylation polymor phism in the metabolic activation of heterocyclic amine mutagens and c arcinogens.