Chemical methods for assessing systemic exposure to dietary heterocyclic amines in man.
A significant proportion of the mutagenic material present in cooked beef is accounted for by 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) which are formed during the cooking of meat. N-hydroxylation catalyzed by CYP1A2 is the major pathway of metbolism of MeIQx and PhIP and is solely responsible for the generation of mutagenic species. Assays for MeIQx and PhIP in foods and body fluids were developed utilising gas chromatography/mass spectrometry with stable isotope labelled analogues as internal standards. Studies using these assays have demonstrated that both MeIQx and PhIP are well absorbed and extensively metabolised following ingestion of amine-containing beef by humans. Studies in which furafylline, a potent and selective inhibitor of human CYP1A2, was administered before ingestion of beef revealed that more than 90% of MeIQx and 70% of PhIP are N-hydroxylated in vivo, probably pre-systemically in the liver. The results demonstrate that unchanged MeIQx and PhIP in urine are accurate and sensitive measures of systemic exposure to the amines.
Davies
D S
DS
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London.
Gooderham
N J
NJ
Murray
S
S
Lynch
A
A
de la Torre
R
R
Segura
J
J
Boobis
A R
AR
D002273:Carcinogens / Q000009:adverse effects* / Q000032:analysis / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005511:Food Handling; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects* / Q000378:metabolism / Q000652:urine; D008460:Meat / Q000009:adverse effects*; D009153:Mutagens / Q000009:adverse effects* / Q000032:analysis / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D011810:Quinoxalines / Q000009:adverse effects* / Q000378:metabolism / Q000652:urine
D002273:Carcinogens; 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; D010088:Oxidoreductases; D019388:Cytochrome P-450 CYP1A2