title: Lower levels of urinary 2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline (MeIQx) in humans with higher CYP1A2 activity.
abstract: Heterocyclic aromatics amines (HAAs), such as 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), are metabolically activated by cytochrome P4501A2 (CYP1A2) and N-acetyltransferase (NAT2). We examined the relationship between CYP1A2 and NAT2 activity and the excretion of total unconjugated MeIQx in 66 healthy subjects. The subjects ate a control diet for 7 days containing lean ground beef cooked at low temperature. On day 8, they were tested for CYP1A2 and NAT2 activity by caffeine phenotyping. On the evening of day 8, subjects consumed lean ground beef cooked at high temperature containing 9.0 ng of MeIQx/g of meat. The subjects ate 3.1-4.0 g meat/kg body wt. Twelve-hour urine samples were collected and MeIQx was measured by gas chromatography-mass spectrometry. Using linear regression analyses, we found that higher CYP1A2 activity was associated with lower levels of total unconjugated MeIQx in the urine (P = 0.008) when adjusted for amount of meat eaten, while NAT2 activity showed no relationship with the latter. This suggest that a greater percentage of MeIQx is converted to metabolites such as the N-hydroxy derivative when CYP1A2 activity is higher. This finding supports the concept that inter-individual variation is CYP1A2 activity may be relevant for cancers associated with exposure to HAAs.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD 20892, USA.
authors.forename: R
authors.initials: R
authors.lastname: Sinha
authors.forename: N
authors.initials: N
authors.lastname: Rothman
authors.forename: S D
authors.initials: SD
authors.lastname: Mark
authors.forename: S
authors.initials: S
authors.lastname: Murray
authors.forename: E D
authors.initials: ED
authors.lastname: Brown
authors.forename: O A
authors.initials: OA
authors.lastname: Levander
authors.forename: D S
authors.initials: DS
authors.lastname: Davies
authors.forename: N P
authors.initials: NP
authors.lastname: Lang
authors.forename: F F
authors.initials: FF
authors.lastname: Kadlubar
authors.forename: R N
authors.initials: RN
authors.lastname: Hoover
mesh_terms: D000328:Adult; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009153:Mutagens / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism*; D011810:Quinoxalines / Q000652:urine*
chemical_list: D002273:Carcinogens; D009153:Mutagens; D011810:Quinoxalines; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019388:Cytochrome P-450 CYP1A2; D001191:Arylamine N-Acetyltransferase