CYP1A2 and NAT2 genotype/phenotype relations and urinary excretion of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in a human dietary intervention study.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mutagenic and carcinogenic heterocyclic amine formed during ordinary cooking, and is subsequently metabolically activated by cytochrome P4501A2 (CYP1A2) and N-acetyltransferase 2 (NAT2). Respective genes encoding for these enzymes, display polymorphic distribution in the human population and are thus believed to cause interindividual differences in cancer risk susceptibility. The present study investigated the influence of dietary exposure and CYP1A2 and NAT2 genotypes and phenotypes on differential urinary PhIP excretion levels in 71 human volunteers after consumption of either a high (7.4 ng/g) or low (1.7 ng/g) dose of PhIP. Urinary PhIP excretion levels were found to reflect recent dietary exposure levels, with average levels of 174% (high dose group) and 127% (low dose group), as compared to pre-feed levels. Urinary caffeine metabolite ratios were significantly different between the two NAT2 genotypes, whereas for CYP1A2, the apparent difference in metabolic ratios between the genotypes was statistically non-significant. Significant correlations were firstly found between the CYP1A2-164A-->C (CYP1A2*1F) polymorphism and differential urinary PhIP excretion levels. Although the found correlations are driven primarily by a small number of subjects possessing the homozygous variant constellation, the strong influence of this genotype indicates that the CYP1A2*1F polymorphism could play an important role in human cancer risk susceptibility.
Moonen
Harald J J
HJ
Department of Health Risk Analysis and Toxicology, University of Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands. h.moonen@ggrat.unimaas.nl
Moonen
Edwin J C
EJ
Maas
Lou
L
Dallinga
Jan W
JW
Kleinjans
Jos C S
JC
de Kok
Theo M C M
TM
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000494:pharmacology; D002273:Carcinogens / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003296:Cooking; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics* / Q000494:pharmacology; D004032:Diet; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000652:urine*; D010641:Phenotype; D011110:Polymorphism, Genetic; D012307:Risk Factors
D002273:Carcinogens; D007093:Imidazoles; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D019388:Cytochrome P-450 CYP1A2; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human