Enzymic and interindividual differences in the human metabolism of heterocyclic amines.
Heterocyclic amines (HAs) present in cooked meat (PhIP and MeIQx) are activated only by CYP1A2 in the liver of most species, including man. This enzyme exhibits marked interindividual differences in its expression, due to induction and possibly also genetically. The absence of CYP1A2 appears to protect from HA-(PhIP and MeIQx) induced cancer, as exemplified by results in the cynomolgus monkey. Differences in the potency of these HAs are not due to differences in the kinetics of their activation. The catalytic efficiency of CYP1A2 towards HAs and their oxidative fate varies amongst species, in both cases increasing the susceptibility of humans compared to that of the rat. Interindividual and inter-organ differences in the further metabolism of N-hydroxy-HAs appear to be important determinants of cancer susceptibility, as does the glutathione S-transferase catalysed detoxication of esters of N-hydroxy-PhIP. There is a need for an effective means of quantifying the in vivo activation of HAs in man to enable the possible risk posed by these compounds to be assessed effectively.
Boobis
A R
AR
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London, United Kingdom.
Gooderham
N J
NJ
Edwards
R J
RJ
Murray
S
S
Lynch
A M
AM
Yadollahi-Farsani
M
M
Davies
D S
DS
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000009:adverse effects / Q000378:metabolism* / Q000633:toxicity; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D005511:Food Handling; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D006900:Hydroxylation; D007093:Imidazoles / Q000009:adverse effects / Q000378:metabolism* / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008461:Meat Products; D009153:Mutagens / Q000009:adverse effects / Q000378:metabolism* / Q000633:toxicity; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D011810:Quinoxalines / Q000009:adverse effects / Q000378:metabolism* / Q000633:toxicity; D013045:Species Specificity
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