Satarug S, Lang M A, Yongvanit P, Sithithaworn P, Mairiang E, Mairiang P, Pelkonen P, Bartsch H, Haswell-Elkins M R
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Thailand.
Cancer Epidemiol Biomarkers Prev. 1996 Oct;5(10):795-800.
The purpose of this study was to examine in vivo the activity of cytochrome P450 (CYP) 2A6, an enzyme capable of activating carcinogens, including N-nitrosodimethylamine, in humans with the carcinogenic liver fluke infection, opisthorchiasis viverrini, before and after treatment with the antiparasitic agent, praziquantel. Coumarin hydroxylase activity of CYP 2A6 was assessed by administering a probe drug, coumarin, and measuring its metabolite, 7-hydroxycoumarin, in urines collected between 0-2 h and 2-4 h of 106 people with varying intensities of Opisthorchis viverrini infection. Five individuals who did not excrete any detectable 7-hydroxy coumarin (and have a genetic defect probably leading to an absence of catalytic activity of the CYP 2A6 protein) were excluded from analysis. Infected people excreted an average of 22.7 mumol of 7-hydroxycoumarin in the first 2 h after taking the drug, whereas the mean of the uninfected group was 19.4 mumol; this difference did not reach statistical significance (P = 0.10). However, a highly significant increase in CYP 2A6-related activity was observed in infected individuals who also had radiological evidence of biliary fibrosis (28.1 mumol) compared to those without (19.4 mumol; P = 0.01). Reassessments of coumarin hydroxylase activity of CYP 2A6 made 2 months after praziquantel treatment showed highly significant reductions in the amount of 7-hydroxycoumarin excreted among the infected groups but no difference in the uninfected group. These results suggest that expression of CYP 2A6 is induced among chronically infected people who also have fibrosis of the intrahepatic bile duct. As already demonstrated in an animal model and now observed in humans for the first time, this increase in CYP 2A6-related enzyme activity may represent an important mechanistic link between inflammatory products of chronic liver fluke infection (e.g., DNA alkylation damage from endogenously formed N-nitrosamines) and the high risk of cholangiocarcinoma faced by infected individuals.
本研究的目的是在体内检测细胞色素P450（CYP）2A6的活性。CYP 2A6是一种能够激活致癌物（包括N-亚硝基二甲胺）的酶。研究对象为感染致癌性肝吸虫——华支睾吸虫的患者，在使用抗寄生虫药物吡喹酮治疗前后，通过给予探针药物香豆素并测量其代谢产物7-羟基香豆素，来评估106名不同华支睾吸虫感染强度患者在0-2小时和2-4小时收集尿液中CYP 2A6的香豆素羟化酶活性。5名未排出任何可检测到的7-羟基香豆素的个体（可能存在导致CYP 2A6蛋白催化活性缺失的基因缺陷）被排除在分析之外。感染患者在服药后的前2小时平均排出22.7微摩尔的7-羟基香豆素，而未感染组的平均值为19.4微摩尔；这种差异未达到统计学显著性（P = 0.10）。然而，与无胆管纤维化影像学证据的感染个体（19.4微摩尔；P = 0.01）相比，有胆管纤维化影像学证据的感染个体中观察到CYP 2A6相关活性显著增加（28.1微摩尔）。吡喹酮治疗2个月后对CYP 2A6香豆素羟化酶活性的重新评估显示，感染组中7-羟基香豆素的排出量显著减少，而未感染组无差异。这些结果表明，在同时患有肝内胆管纤维化的慢性感染患者中，CYP 2A6的表达被诱导。正如在动物模型中已经证明的，现在首次在人类中观察到，CYP 2A6相关酶活性的增加可能代表慢性肝吸虫感染的炎症产物（例如内源性形成的N-亚硝胺导致的DNA烷基化损伤）与感染个体面临的胆管癌高风险之间的重要机制联系。
