ACTIVATION OF HETEROCYCLIC AROMATIC-AMINES BY RAT AND HUMAN LIVER-MICROSOMES AND BY PURIFIED RAT AND HUMAN CYTOCHROME-P450 1A2

The dietary mutagens 2-amino-3,8-dimethylimidazo[4,5-f]quinox (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) are activa ted to genotoxins by rat and human liver cytochrome P450 (P450) 1A1- a nd 1A2-mediated N-oxidation. Immunoquantitation of 51 human liver samp les revealed a wide range in P450 1A2 expression (10-250 pmol/mg of mi crosomal protein, median 71 pmol/mg), with 39% of the livers containin g > 100 pmol/mg of protein. There was no evidence for expression of P4 50 1A1 (il pmol/mg of protein). P450 1A2 levels were correlated to MeI Qx and PhIP N-oxidation rates (r = 0.83, 0.73, respectively). In male Fischer-344 and Sprague-Dawley rats, hepatic P450 1A2 ranged from 5 to 35 pmol/mg of protein, while P450 1A1 was <1 pmol/mg. Animal pretreat ment with S-methylcholanthrene, beta-naphthoflavone, or polychlorinate d biphenyls (PCB) resulted inasmuch as 340-fold and >1000-fold inducti on of P450 1A2 and 1A1, respectively, and a 220-fold increase in N-oxi dation activity. Approximately 20% of the human samples were as active in N-oxidation and conversion of MeIQx to bacterial mutagens as micro somes of PCB-pretreated rats [3-4 nmol of NHOH-MeIQx formed min(-1) (m g of protein)(-1)]. In contrast, microsomes from PCB-treated rats disp layed higher rates of PhIP N-oxidation and activation to mutagens than the most active human liver microsomes [8-24 vs 2-4 nmol of HNOH-PhIP formed min(-1) (mg of protein)(-1)]. Recombinant human P450 1A2 showe d catalytic efficiencies of MeIQx and PhIP N-oxidation that were 10-19 -fold higher than purified rat P450 1A2. Cytochrome P450 1A2 expressio n in rodent and human liver tissue varies greatly and there are consid erable differences between the enzymes in the two species in the activ ation of some heterocyclic aromatic amines, which must be considered w hen assessing human health risk.