严重的2,3,7,8-四氯二苯并对二恶英（TCDD）中毒：关于肝细胞色素P450 1A2诱导测量的见解

Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: insights into the measurement of hepatic cytochrome P450 1A2 induction.

作者信息

Abraham Klaus, Geusau Alexandra, Tosun Yalcin, Helge Hans, Bauer Steffen, Brockmöller Jürgen

机构信息

Department of Pediatric Pneumology and Immunology, Institute of Clinical Pharmacology, Charité, Humboldt University Berlin, Augustenburger Platz 1, 13 153 Berlin, Germany.

出版信息

Clin Pharmacol Ther. 2002 Aug;72(2):163-74. doi: 10.1067/mcp.2002.126408.

DOI:10.1067/mcp.2002.126408

PMID:12189363

Abstract

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 (1U), and 1-methylxanthine (1X) 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.

摘要

目的

准确在体内定量芳烃受体介导的人类细胞色素P450 1A2（CYP1A2）诱导作用一直是个长期存在的问题。我们比较了咖啡因试验的几种改良方法在酶诱导作用极高、极低或无诱导作用的受试者中测量CYP1A2活性的性能。

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名中度暴露的男性以及50名对照受试者（30名不吸烟者和20名重度吸烟者）中测量CYP1A2活性。给予试验剂量后，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情况。

结果

在高度TCDD暴露者中，呼气试验结果（累积15分钟剂量）、咖啡因总清除率、血清代谢物比率对黄嘌呤/咖啡因（给药后30分钟和120分钟）以及尿液代谢物比率5-乙酰氨基-6-甲酰氨基-3-甲基尿嘧啶（AFMU）、1-甲基尿酸（1U）和1-甲基黄嘌呤（1X）之和与1,7-二甲基尿酸（17U）相比，显示CYP1A2活性比不吸烟者的平均值高8至10倍。相比之下，两种以母体物质为分母的咖啡因尿液代谢物比率未反映CYP1A2酶诱导情况。这些比率强烈依赖于尿流。对于呼气试验，只有在短采样期（如给药后15分钟）评估的结果显示出高诱导作用。与不吸烟者相比，所有试验在吸烟者中均观察到更高的平均值（最高1.8倍）。