DETERMINATION OF CYP1A2 AND NAT2 PHENOTYPES IN HUMAN-POPULATIONS BY ANALYSIS OF CAFFEINE URINARY METABOLITES
DETERMINATION OF CYP1A2 AND NAT2 PHENOTYPES IN HUMAN-POPULATIONS BY ANALYSIS OF CAFFEINE URINARY METABOLITES
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DOI：
10.1097/00008571-199206000-00003
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发表时间：
1992-06-01
期刊：
影响因子：
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通讯作者：
KADLUBAR, FF
中科院分区：
文献类型：
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作者：
BUTLER, MA;LANG, NP;KADLUBAR, FF
人类膀胱癌和结直肠癌发病率的巨大差异部分归因于与接触致癌芳香胺和杂环胺相关的代谢因素。催化 N-氧化的细胞色素 P-4501A2 (CYP1A2) 和催化 N- 和 O-乙酰化的乙酰转移酶 (NAT2) 似乎都以多态性分布在人群中；慢速和快速 NAT2 表型被认为是这些癌症的危险因素。咖啡因也被证明会被 CYP1A2 进行 3-去甲基化，并被多态性 NAT2 进一步乙酰化为 5-乙酰氨基-6-甲酰氨基-3-甲基尿嘧啶 (AFMU)。在本报告中，我们描述了一种代谢表型分析程序，可用于同时确定肝脏 CYP1A2 和 NAT2 表型。对于 NAT2 表型，我们确认了 AFMU/1-甲基黄嘌呤的尿液摩尔比的有效使用，即使在碱性尿液中也是如此。对于 CYP1A2 表型，摄入咖啡因后 4-5 小时测定的 [1,7-二甲基黄嘌呤 + 1,7-二甲基尿酸]/咖啡因的尿摩尔比通过对 12 名受试者的药代动力学分析确定，与咖啡因 3-去甲基化速率常数的相关性比之前建议的其他比率更好（r = 0.73；p = 0.007）。然后使用该程序确定来自阿肯色州 (n = 101)、意大利 (n = 95) 和中国 (n = 78) 的受试者的 CYP1A2 表型。非吸烟者的统计和概率分析表明，CYP1A2 活性不呈正态分布，呈三峰分布。这种三峰性允许任意指定慢速、中速和快速表型，在不同人群中，慢速表型的范围为 12-13%，中速表型为 51-67%，快速表型为 20-37%。一项为期 5 天或 5 周期间对 13 名受试者进行的可重复性研究表明，除一个例外外，个体内变异并没有改变这种 CYP1A2 表型分类。在阿肯色州和意大利吸烟者（金色烟草）中观察到的咖啡因代谢物比例增加也证实了吸烟对 CYP1A2 的诱导作用。然而，意大利黑烟吸烟者和中国吸烟者似乎并未受到诱导。此外，对阿肯色州和意大利金发吸烟者的概率分析无法区分表型，这显然是酶诱导的结果。
The wide variations in urinary bladder and colo-rectal cancer incidence in humans have been attributed in part to metabolic factors associated with exposure to carcinogenic aromatic and heterocyclic amines. Cytochrome P-4501A2 (CYP1A2), which catalyses N-oxidation, and acetyltransferase (NAT2) which catalyses N- and O-acetylation, both appear to be polymorphically distributed in human populations; and slow and rapid NAT2 phenotypes have been implicated as risk factors for these cancers. Caffeine has also been shown to undergo 3-demethylation by CYP1A2, and it is further acetylated to 5-acetylamino-6-formylamino-3-methyluracil (AFMU) by the polymorphic NAT2. In this report, we describe a metabolic phenotyping procedure that can be used to determine concomitantly the hepatic CYP1A2 and NAT2 phenotypes. For the NAT2 phenotype, we confirm the valid use of the urinary molar ratio of AFMU/1-methylxanthine, even in alkaline urines. For the CYP1A2 phenotype, the urinary molar ratio of [1,7-dimethylxanthine + 1,7-dimethyluric acid]/caffeine, taken at 4-5 h after caffeine ingestion, was identified from pharmacokinetic analyses of 12 subjects as being better correlated (r = 0.73; p = 0.007) with the rate constant for caffeine 3-demethylation than other previously suggested ratios. This procedure was then used to determine the CYP1A2 phenotype in subjects from Arkansas (n = 101), Italy (n = 95), and China (n = 78). Statistical and probit analyses of nonsmokers indicated that the CYP1A2 activity was not normally distributed and appeared trimodal. This trimodality allowed arbitrary designation of slow, intermediate, and rapid phenotypes, which ranged from 12-13% slow, 51-67% intermediate, and 20-37% rapid, in the different populations. A reproducibility study of 13 subjects over a 5 day or 5 week period showed that, with one exception, intraindividual variability did not alter this CYP1A2 phenotypic classification. Induction of CYP1A2 by cigarette smoking was also confirmed by the increased caffeine metabolite ratios observed in the Arkansas and Italian smokers (blonde tobacco). However, Italian smokers of black tobacco and Chinese smokers did not appear to be induced. Furthermore, probit analyses of Arkansas and Italian blonde tobacco smokers could not discriminate between phenotypes, apparently as a consequence of enzyme induction.