Enzymatic studies of the activation of heterocyclic food mutagens in man.
2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are amongst the most abundant of the heterocyclic aromatic amines formed during the cooking of beef. Both compounds are genotoxic and carcinogenic in rodents. These effects are manifested only after activation of the amines by P450. Human liver is very active at converting these amines to mutagenic products. Studies in vitro have established that, for both amines, mutagenicity with human liver microsomes is entirely via the N-hydroxylamine, essentially the only oxidation product of either amine. Both N-hydroxylation and mutagenicity of the amines can be almost completely inhibited by furafylline, a potent and highly selective inhibitor of CYP1A2 in man. These data, together with the work of others, show that the N-hydroxylation and hence the mutagenicity of both MeIQx and PhIP in man is catalyzed almost exclusively by CYP1A2. Liver from cynomolgus monkeys, unlike that from humans and marmosets, is very poor at activating MeIQx or PhIP to mutagenic products. Studies with anti-peptide antibodies of defined specificity revealed that this is due to the absence of CYP1A2, suggesting that this species should not be used to assess the possible risk posed to man by these amines. The marmoset would be a better species for this purpose.
Boobis
A R
AR
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London, England.
Gooderham
N J
NJ
Rich
K J
KJ
Zhao
K
K
Edwards
R J
RJ
Murray
B P
BP
Lynch
A M
AM
Murray
S
S
Davies
D S
DS
D000818:Animals; D001711:Biotransformation; D002144:Callithrix; D002417:Cattle; D003296:Cooking; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D008252:Macaca fascicularis; D008460:Meat; D008862:Microsomes, Liver / Q000201:enzymology*; D009153:Mutagens / Q000378:metabolism*; D011810:Quinoxalines / Q000378:metabolism*; D011817:Rabbits; D013379:Substrate Specificity
D006571:Heterocyclic Compounds; D007093:Imidazoles; D009153:Mutagens; D011810:Quinoxalines; 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; D019388:Cytochrome P-450 CYP1A2