Systemic exposure to dietary heterocyclic amines in man.
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-I-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are formed during the cooking of meat and account for a significant proportion of the mutagenic material present in cooked beef. The amines are not directly mutagenic but are converted to active intermediates by P450. Studies in vitro with human liver have shown that N-hydroxylation catalyzed by CYP1A2 is the major pathway of oxidation of MeQx and PhIP and is solely responsible for the generation of mutagenic species. In the studies reported in this paper it is demonstrated that both MelIQx and PhIP are well absorbed and extensively metabolized following ingestion of amine-containing beef by humans. Experiments with furafylline, a potent and selective inhibitor of human CYP1A2, reveal that more than 90% of MeIQx and 70% of PhIP are N-hydroxylated in vivo, probably presystemically in the liver.
Davies
D S
DS
Department of Clinical Pharmacology, Royal Postgraduate Medical School London, England.
Gooderham
N J
NJ
Murray
S
S
Lynch
A
A
de la Torre
R
R
Segura
J
J
Boobis
A R
AR
D000818:Animals; D001711:Biotransformation; D002417:Cattle; D003296:Cooking; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004032:Diet; D004781:Environmental Exposure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006358:Hot Temperature; D006801:Humans; D007093:Imidazoles / Q000378:metabolism* / Q000493:pharmacokinetics; D008460:Meat; D008657:Metabolic Clearance Rate; D009153:Mutagens / Q000378:metabolism* / Q000493:pharmacokinetics; D011810:Quinoxalines / Q000378:metabolism* / Q000493:pharmacokinetics; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology
D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009153:Mutagens; D011810:Quinoxalines; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D013806:Theophylline; C050131:furafylline; D019388:Cytochrome P-450 CYP1A2