Hadidi H, Irshaid Y, Vågbø C B, Brunsvik A, Cholerton S, Zahlsen K, Idle J R
Department of Pharmacology, Faculty of Medicine, Jordan University of Science and Technology, Irbid.
Eur J Clin Pharmacol. 1998 Jul;54(5):437-41. doi: 10.1007/s002280050489.
To determine the variability of coumarin 7- and 3-hydroxylation in a human population and to evaluate the evidence for the existence of genetic polymorphism in these pathways. 7-Hydroxylation of coumarin is considered to be a detoxication pathway, whilst 3-hydroxylation, which predominates in rats, leads to hepatotoxicity in the rat. Coumarin metabolic phenotypes could aid in refining the risk evaluation for humans of dietary and environmental exposure to coumarin and for the chronic use of coumarin in high doses as a drug to treat lymphoedema and certain cancers.
Healthy male and female Jordanian volunteers (n = 103) were administered 2 mg coumarin by mouth and collected their 0-8-h urines. These, together with pre-dose blank urines, were analysed by selected-ion monitoring gas chromatography mass spectrometry for their content of the coumarin metabolites 7-hydroxycoumarin (70HC) and 2-hydroxyphenylacetic acid (2OHPAA), the latter arising from the 3-hydroxylation pathway.
After coumarin administration, excretion of both 70HC and 2OHPAA was highly variable. A coumarin metabolic ratio (2OHPAA/7OHC) was suggestive of polymorphism. At least one subject had a metabolic response similar to an individual known to be both phenotypically and genotypically (CYP2A6 gene) 7-hydroxylation-deficient.
In the light of the finding of high variability and possible polymorphism in both the 7- and 3-hydroxylation of coumarin in a human population. we recommend a reappraisal of the risk evaluation of human exposure to coumarin, particularly in pharmaceutical doses.
确定人群中香豆素7-羟基化和3-羟基化的变异性，并评估这些代谢途径中存在基因多态性的证据。香豆素的7-羟基化被认为是一条解毒途径，而在大鼠中占主导的3-羟基化会导致大鼠肝毒性。香豆素代谢表型有助于优化对人类因饮食和环境接触香豆素以及长期大剂量使用香豆素作为治疗淋巴水肿和某些癌症药物的风险评估。
对103名健康的约旦男女志愿者口服2毫克香豆素，并收集其0至8小时的尿液。将这些尿液与给药前的空白尿液一起，通过选择离子监测气相色谱质谱法分析香豆素代谢物7-羟基香豆素（70HC）和2-羟基苯乙酸（2OHPAA）的含量，后者来自3-羟基化途径。
服用香豆素后，70HC和2OHPAA的排泄量高度可变。香豆素代谢率（2OHPAA/7OHC）提示存在多态性。至少有一名受试者的代谢反应与一名已知在表型和基因型（CYP2A6基因）上均缺乏7-羟基化的个体相似。
鉴于在人群中发现香豆素7-羟基化和3-羟基化均具有高变异性和可能的多态性，我们建议重新评估人类接触香豆素的风险评估，尤其是在药物剂量方面。
