Assessing human risk to heterocyclic amines.
Heterocyclic amines such as MeIQx and PhIP are potent genotoxic chemicals which are formed at part per billion levels when meat is cooked. Using assays based on gas chromatography/mass spectrometry with stable isotope labelled analogues as internal standards we have demonstrated MeIQx and PhIP, are efficiently absorbed into the systemic circulation after ingestion of fried beef. Using a potent and selective inhibitor of human CYP1A2, furafylline, we have shown that N-hydroxylation catalysed by this enzyme is the major pathway of metabolism of MeIQx and PhIP and is solely responsible for their oxidation to mutagenic species. This is in contrast to the situation in laboratory animals in which both activation by N-hydroxylation and deactivation by C-oxidation occurs. When furafylline was administered to human volunteers before ingestion of fried beef, we showed that > 90% of MeIQx and approximately 70% of PhIP elimination could be inhibited, demonstrating the extent to which activation occurred in man. MeIQx is a very powerful mutagen in bacterial assays whereas PhIP is a more potent mammalian cell mutagen. Using a mammalian cell target gene, hprt, we have shown that PhIP induces a characteristic mutational 'fingerprint' which is identical to that detected in the Apc gene of 5/8 colonic tumours induced by PhIP in rats. These studies support a biological association between HA exposure and diet-related tumours but emphasise that information obtained from animal studies does not always reflect the situation in humans.
Gooderham
N J
NJ
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London, UK.
Murray
S
S
Lynch
A M
AM
Yadollahi-Farsani
M
M
Zhao
K
K
Rich
K
K
Boobis
A R
AR
Davies
D S
DS
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003296:Cooking; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D008460:Meat; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism*; D011804:Quinolines / Q000378:metabolism*; D011817:Rabbits; D012306:Risk; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology
D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009153:Mutagens; D011804:Quinolines; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D013806:Theophylline; C050131:furafylline; D019388:Cytochrome P-450 CYP1A2; C036989:2-amino-3,4-dimethylimidazo(4,5-f)quinoline