CONTRIBUTION OF CYP1A1, AND CYP1A2 TO THE ACTIVATION OF HETEROCYCLIC AMINES IN MONKEYS AND HUMAN

The activation of heterocyclic amines to mutagenic products by hepatic microsomal fractions from cynomolgus monkey, marmoset monkey and man, vas compared with the respective levels of cytochrome P450 enzymes CYP 1A1 and CYP1A2. The rate of activation of 2-amino-3,8-dimethylimidazo[ 4,5-f] quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f] quinoline ( IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) to mut agens by hepatic microsomal fraction from cynomolgus monkey was very l ow. This was associated with a lack of constitutive expression of CYP1 A1 and CYP1A2. In contrast, human hepatic microsomal fraction readily activates these heterocyclic amines and this is associated with consti tutive expression of CYP1A2. Treatment of cynomolgus monkey with 2,3,7 ,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a very modest induction o f CYP1A2, and a small increase in the activation of MeIQx and IQ. Howe ver, there was marked induction of CYP1A1 which was accompanied by > 1 0-fold increases in PhIP activation and 7-ethoxyresorufin O-deethylase (EROD), 7-methoxyresorufin O-demethylase (MROD) and aryl hydrocarbon hydroxylase activities. Following treatment of cynomolgus monkey with 3-methylcholanthrene, induction of CYP1A1, but not CYP1A2, was evident . In untreated marmoset monkey the activations of MeIQx and PhIP, as w ell as phenacetin O-deethylase, EROD, MROD and aryl hydrocarbon hydrox ylase activities, are similar to those in man, although the activation s of IQ and coumarin 7-hydroxylase activity are lower than in man. The presence of constitutive CYP1A2, and the absence of CYP1A1, in the li ver of this species correspond to the situation in man. Treatment of m armoset monkey with TCDD results in increased CYP1A2 levels (4-fold), accompanied by proportional increases in the activation of MeIQx and I Q and phenacetin O-deethylase, EROD and MROD activities. The activatio n of PhIP is increased disproportionately, by 8-fold, most likely due to the activity of CYP1A1 which is also induced by TCDD in this specie s. Overall, the hepatic metabolism of heterocyclic amines by CYP1A enz ymes in the untreated marmoset monkey resembles that in human more clo sely than that in the cynomolgus monkey. Therefore, marmoset monkey ma y be a more suitable model than the cynomolgus monkey for carcinogenic ity studies involving MeIQx and PhIP, but not IQ.