Lynch A M, Knize M G, Boobis A R, Gooderham N J, Davies D S, Murray S
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London, United Kingdom.
Cancer Res. 1992 Nov 15;52(22):6216-23.
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.
在牛肉烹饪过程中，会形成具有基因毒性的杂环芳香胺，如2-氨基-3,8-二甲基咪唑并[4,5-f]喹喔啉（MeIQx）、2-氨基-3,4,8-三甲基咪唑并[4,5-f]喹喔啉（DiMeIQx）和2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）。关于这些化合物在人体中的代谢情况以及影响其代谢的因素，人们了解甚少。我们开发了基于毛细管柱气相色谱-负离子质谱的检测方法，该方法能够使用稳定同位素标记的类似物同时测定熟肉和人体尿液中的MeIQx、DiMeIQx和PhIP。在14个月的时间里，邀请了10名正常、健康的男性志愿者分四次食用标准熟肉餐（400 - 450克瘦牛肉，在烤盘上煎成肉饼）。食用测试餐后，在0至8小时收集尿液，在此期间所有游离胺被排出，并对尿液进行MeIQx、DiMeIQx和PhIP分析。受试者摄入了240±9（SEM）克熟肉，其中每克肉含有2.2±0.2纳克MeIQx、0.7±0.1纳克DiMeIQx和16.4±2.1纳克PhIP。根据尿液中未变化排出的摄入胺的百分比评估相对全身生物利用度的变异性。受试者尿液中排出的未变化的MeIQx占摄入MeIQx的2.1±1.1%，排出的未变化的PhIP占摄入PhIP的1.1±0.5%。尿液中DiMeIQx的含量（如果存在）低于我们检测方法的灵敏度（20皮克/毫升），在所有分析样本中均未检测到。无论剂量如何，每个个体受试者尿液中未变化的MeIQx或PhIP的排泄量（以摄入剂量的百分比表示）保持恒定。MeIQx的个体内变异系数（28.4%）和PhIP的个体内变异系数（23.7%）较低，两种化合物的合并日间（个体内）变异系数分别仅为19%和3.4%。相比之下，个体间（日内）变异更大，MeIQx的合并变异系数为145%，PhIP的合并变异系数为71%。基于这些研究，应该可以使用MeIQx和PhIP的排泄百分比来评估这些化合物在人体中的相对生物利用度。
