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 was compared with the respective levels of cytochrome P450 enzymes CYP1A1 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 mutagens by hepatic microsomal fraction from cynomolgus monkey was very low. This was associated with a lack of constitutive expression of CYP1A1 and CYP1A2. In contrast, human hepatic microsomal fraction readily activates these heterocyclic amines and this is associated with constitutive expression of CYP1A2. Treatment of cynomolgus monkey with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a very modest induction of CYP1A2, and a small increase in the activation of MeIQx and IQ. However, there was marked induction of CYP1A1 which was accompanied by > 10-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 well as phenacetin O-deethylase, EROD, MROD and aryl hydrocarbon hydroxylase activities, are similar to those in man, although the activations of IQ and coumarin 7-hydroxylase activity are lower than in man. The presence of constitutive CYP1A2, and the absence of CYP1A1, in the liver of this species correspond to the situation in man. Treatment of marmoset monkey with TCDD results in increased CYP1A2 levels (4-fold), accompanied by proportional increases in the activation of MeIQx and IQ and phenacetin O-deethylase, EROD and MROD activities. The activation of PhIP is increased disproportionately, by 8-fold, most likely due to the activity of CYP1A1 which is also induced by TCDD in this species. Overall, the hepatic metabolism of heterocyclic amines by CYP1A enzymes in the untreated marmoset monkey resembles that in human more closely than that in the cynomolgus monkey. Therefore, marmoset monkey may be a more suitable model than the cynomolgus monkey for carcinogenicity studies involving MeIQx and PhIP, but not IQ.
Edwards
R J
RJ
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London, UK.
Murray
B P
BP
Murray
S
S
Schulz
T
T
Neubert
D
D
Gant
T W
TW
Thorgeirsson
S S
SS
Boobis
A R
AR
Davies
D S
DS
D000818:Animals; D001711:Biotransformation; D002144:Callithrix; D002273:Carcinogens / Q000378:metabolism / Q000493:pharmacokinetics; D019388:Cytochrome P-450 CYP1A2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000493:pharmacokinetics*; D015151:Immunoblotting; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism / Q000493:pharmacokinetics*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011804:Quinolines / Q000378:metabolism / Q000493:pharmacokinetics*; D011810:Quinoxalines / Q000378:metabolism / Q000493:pharmacokinetics*; D013045:Species Specificity
D002273:Carcinogens; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D009153:Mutagens; D011804:Quinolines; D011810:Quinoxalines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D003577:Cytochrome P-450 Enzyme System; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D010088:Oxidoreductases; D019388:Cytochrome P-450 CYP1A2