Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication:: Insights into the measurement of hepatic cytochrome P450 1A2 induction
Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication:: Insights into the measurement of hepatic cytochrome P450 1A2 induction
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DOI：
10.1067/mcp.2002.126408
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发表时间：
2002-08-01
影响因子：
6.7
通讯作者：
Brockmöller, J
中科院分区：
文献类型：
--
作者：
Abraham, K;Geusau, A;Brockmöller, J
目的：对人体中芳烃受体介导的细胞色素 P450 1A2 (CYP1A2) 诱导的正确体内定量是一个长期存在的问题。我们比较了用于测量酶诱导异常高、低或缺乏的受试者中 CYP1A2 活性的咖啡因测试的几种修改的性能。方法：在 2 名高度暴露于 2,3,7,8-四氯二苯并-对二恶英 (TCDD) 的女性、1 名中度暴露于 2,3,7,8-四氯二苯并-对二恶英 (TCDD) 的女性以及 50 名对照受试者（30 名非吸烟者和 20 名重度吸烟者）中测量了 CYP1A2 活性。施用测试剂量后，通过碳 13 呼气试验、总清除率以及几种血清和尿液代谢物比率检测咖啡因去甲基化。结果：在 TCDD 高度暴露者中，呼气试验结果（累积 15 分钟剂量）、总咖啡因清除率、血清代谢比副黄嘌呤/咖啡因（施用后 30 分钟和 120 分钟）以及尿代谢比总和5-乙酰氨基-6-甲酰氨基-3-甲基尿嘧啶 (AFMU)、1-甲基尿酸 (IU) 和 1-甲基黄嘌呤 (IX) 与 1,7-二甲基尿酸 (17U) 相比，CYP1A2 活性比非吸烟者的平均值高 8 至 10 倍。相比之下，以母体物质为分母的两个咖啡因尿代谢比并未反映CYP1A2酶的诱导。这些比率很大程度上取决于尿流量。对于呼气测试，仅评估短采样周期（例如，施用后15分钟）的结果显示出高感应。与非吸烟者相比，在所有测试中，吸烟者均观察到较高的平均值（最大 1.8 倍）。结论：在高浓度 TCDD 暴露后，人类肝脏 CYP1A2 活性可诱导至少 10 倍。中等程度的 TCDD 暴露（血脂中高达 1000 ppt）不会引起 CYP1A2 诱导，可通过测量来单独区分背景暴露。因此，直接定量此类毒素更具特异性和敏感性。
Objective: The correct in vivo quantification of aryl hydrocarbon receptor-mediated induction of cytochrome P450 1A2 (CYP1A2) in humans is a long-standing question. We compared the performance of several modifications of the caffeine test for measurement of CYP1A2 activity in subjects with exceptionally high, low, or absent enzyme induction.Methods: CYP1A2 activity was measured in 2 women highly exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in 1 man moderately exposed, and in 50 control subjects (30 nonsmokers and 20 heavy smokers). After the application of a test dose, caffeine demethylation was detected with the carbon 13 breath test, the total clearance, and several serum and urinary metabolite ratios.Results: In the highly TCDD-exposed persons, results of the breath test (cumulative 15-minute dose), the total caffeine clearance, the serum metabolic ratio paraxanthine/caffeine (30 and 120 minutes after application), and the urinary metabolic ratio sum of 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methyluric acid (IU), and 1-methylxanthine (IX) over 1,7-dimethyluric acid (17U) showed a CYP1A2 activity 8 to 10 times higher than the mean of nonsmokers. In contrast, two caffeine urinary metabolic ratios with the parent substance in the denominator did not reflect the CYP1A2 enzyme induction. These ratios strongly depended on urine flow. For the breath test, only results evaluated for a short sampling period (eg, 15 minutes after application) revealed the high induction. Compared with nonsmokers, higher mean values (maximally 1.8 times) were observed in smokers with all tests.Conclusion: After high TCDD exposure, hepatic CYP1A2 activity is inducible at least 10 times in humans. Moderate TCDD exposure (up to 1000 ppt in blood fat) does not cause a CYP1A2 induction that can be measured to differentiate from background exposure individually. Therefore direct quantification of such toxins is more specific and sensitive.