Heterocyclic amines: evaluation of their role in diet associated human cancer.
1. Heterocyclic amines are formed in parts per billion levels when meat is cooked. 2. The heterocyclic amines MeIQx and PhIP are efficiently absorbed into the systemic circulation after ingestion of cooked food. 3. We have shown that MeIQx and PhIP, both in vitro and in vivo, are substrates for human hepatic CYP1A2, which exclusively and efficiently catalyses their conversion to genotoxic hydroxylamines. 4. MeIQx and PhIP are promutagens. MeIQx is a very powerful bacterial mutagen 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'. 5. MeIQx and PhIP are carcinogenic in bioassays. The PhIP mutational 'fingerprint' has been detected in the Apc gene of 5/8 colonic tumours induced by PhIP in rats.
Gooderham
N J
NJ
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London, UK.
Murray
S
S
Lynch
A M
AM
Edwards
R J
RJ
Yadollahi-Farsani
M
M
Bratt
C
C
Rich
K J
KJ
Zhao
K
K
Murray
B P
BP
Bhadresa
S
S
Crosbie
S J
SJ
Boobis
A R
AR
Davies
D S
DS
D000818:Animals; D001682:Biological Availability; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity*; D004032:Diet; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000633:toxicity*; D008460:Meat / Q000032:analysis*; D009153:Mutagens / Q000493:pharmacokinetics / Q000633:toxicity; D009369:Neoplasms / Q000139:chemically induced*; D011810:Quinoxalines / Q000493:pharmacokinetics / Q000633:toxicity*
D002273:Carcinogens; 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