title: Intra- and interindividual variability in systemic exposure in humans to 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline and 2-amino-1-methyl- 6-phenylimidazo[4,5-b]pyridine, carcinogens present in cooked beef.
abstract: During the cooking of beef, the genotoxic heterocyclic aromatic amines 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are formed. Little is known about the fate of these compounds in humans or the factors affecting it. We have developed assays based on capillary column gas chromatography-negative ion mass spectrometry capable of the simultaneous measurement of MeIQx, DiMeIQx, and PhIP in cooked meat and in human urine using stable isotope labeled analogues. Ten normal, healthy male volunteers were invited to consume a standard cooked meat meal (400-450 g lean beef, cooked as patties on a griddle hotplate) on four separate occasions over a period of 14 months. Following consumption of the test meals, urine was collected from 0 to 8 h, during which time all free amines were excreted and analyzed for MeIQx, DiMeIQx, and PhIP. Subjects ingested 240 +/- 9 (SEM) g cooked meat, which contained 2.2 +/- 0.2 ng MeIQx/g meat, 0.7 +/- 0.1 ng DiMeIQx/g meat, and 16.4 +/- 2.1 ng PhIP/g meat. The variability in relative systemic bioavailability was assessed from the percentage of ingested amine excreted unchanged in the urine. Subjects excreted 2.1 +/- 1.1% of MeIQx and 1.1 +/- 0.5% of PhIP ingested as unchanged amine in the urine. Levels of DiMeIQx in urine, if present, were below the sensitivity of our assay (20 pg/ml) and could not be detected in any of the samples analyzed. Irrespective of dose, urinary excretion of unchanged MeIQx or PhIP (expressed as a percentage of the ingested dose) remained constant for each individual subject. The intraindividual coefficients of variation for MeIQx (28.4%) and PhIP (23.7%) were low and the pooled interday (intrasubject) coefficients of variation for both compounds were only 19 and 3.4%, respectively. In contrast, inter-subject (intraday) variation was greater, with pooled coefficients of variation of 145% for MeIQx and 71% for PhIP. Based on these studies, it should be possible to use the percentage excretion of MeIQx and PhIP to assess the relative bioavailability of these compounds in humans.
authors.affiliation: Department of Clinical Pharmacology, Royal Postgraduate Medical School, London, United Kingdom.
authors.forename: A M
authors.initials: AM
authors.lastname: Lynch
authors.forename: M G
authors.initials: MG
authors.lastname: Knize
authors.forename: A R
authors.initials: AR
authors.lastname: Boobis
authors.forename: N J
authors.initials: NJ
authors.lastname: Gooderham
authors.forename: D S
authors.initials: DS
authors.lastname: Davies
authors.forename: S
authors.initials: S
authors.lastname: Murray
mesh_terms: D000328:Adult; D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics*; D002417:Cattle; D003296:Cooking; D008401:Gas Chromatography-Mass Spectrometry; D014644:Genetic Variation / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics* / Q000652:urine; D007206:Individuality; D008297:Male; D008460:Meat / Q000009:adverse effects / Q000032:analysis*; D009153:Mutagens / Q000493:pharmacokinetics*; D011810:Quinoxalines / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: 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; C042052:2-amino-3,7,8-trimethylimidazo(4,5-f)quinoxaline