Effects of cigarette smoking and carbon monoxide on chlorzoxazone and caffeine metabolism
Effects of cigarette smoking and carbon monoxide on chlorzoxazone and caffeine metabolism
复制标题
DOI：
10.1016/j.clpt.2003.07.001
复制
发表时间：
2003-11-01
影响因子：
6.7
通讯作者：
Jacob, P
中科院分区：
文献类型：
--
作者：
Benowitz, NL;Peng, M;Jacob, P
目标.我们的目的是研究吸烟对氯唑沙宗和咖啡因作为细胞色素P450（CYP1A2）2E1、CYP1A2、黄嘌呤氧化酶和N-乙酰转移酶-2活性探针的处置动力学的影响，并检验一氧化碳通过这些途径抑制药物代谢的假设。在3种治疗条件下对12名吸烟者进行了研究，每种治疗条件持续7天，在此期间，他们吸烟，呼吸一氧化碳以达到与吸烟相关的碳氧血红蛋白水平，或呼吸空气。在每种治疗条件下，受试者口服氯唑沙宗（250 mg）和咖啡因（250 mg），测量处置动力学和尿液代谢产物。与空气条件相比，吸烟显著诱导氯唑沙宗的代谢（口服清除率，5.9 +/-1.5 mL。min（-1）。kg（-1）vs 4.8 +/-1.0 mL。min（-1）。kg（-1），P <.005）和咖啡因（2.0 +/-0.8 mL. min（-1）。kg（-1）vs 1.5 +/-0.7 mL。min（-1）。kg（-1，P <.001），但对反映黄嘌呤氧化酶和N-乙酰转移酶-2活性的咖啡因尿代谢物比率没有影响。吸烟诱导代谢的程度存在相当大的个体差异，特别是当吸烟影响氯唑沙宗时（口服清除率的变化范围为-10%至+71%）。一氧化碳对氯唑沙宗或咖啡因代谢或咖啡因代谢谱没有影响。结论。这项研究提供了新的证据表明，吸烟加速氯唑沙宗代谢，最有可能反映诱导CYP2E1活性，在人类。吸烟诱导CYP2E1活性可能导致烟草诱导的癌症、酒精诱导的肝病和对乙酰氨基酚肝毒性的风险。
Objectives. Our objectives were to examine the effects of cigarette smoking on the disposition kinetics of chlorzoxazone and caffeine as probes of cytochrome P450 (CYP) 2E1, CYP1A2, xanthine oxidase, and N-acetyltransferase-2 activity and to test the hypothesis that carbon monoxide inhibits drug metabolism via these pathways.Methods. Twelve cigarette smokers were studied in 3 treatment conditions, each lasting 7 days, during which they smoked cigarettes, breathed carbon monoxide to achieve carboxyhemoglobin levels similar to those associated with cigarette smoking, or breathed air. In each treatment condition, subjects received oral chlorzoxazone (250 mg) and caffeine (250 mg) with measurement of disposition kinetics and urine metabolite profiles.Results. Compared with the air condition, cigarette smoking significantly induced the metabolism of chlorzoxazone (oral clearance, 5.9 +/- 1.5 mL . min(-1) . kg(-1) versus 4.8 +/- 1.0 mL . min(-1) . kg(-1), P < .005) and caffeine (2.0 +/- 0.8 mL . min(-1) . kg(-1) versus 1.5 +/- 0.7 mL . min(-1) . kg(-1), P < .001) but had no effect on caffeine urine metabolite ratios that reflect xanthine oxidase and N-acetyltransferase-2 activity. Considerable individual variability was noted in the extent of induction of metabolism by cigarette smoking, particularly as it affects chlorzoxazone (change in oral clearance ranged from -10% to +71%). Carbon monoxide had no effect on chlorzoxazone or caffeine metabolism or caffeine metabolic profile.Conclusions. This study provides novel evidence that cigarette smoking accelerates chlorzoxazone metabolism, most likely reflecting induction of CYP2E1 activity, in humans. Induction of CYP2E1 activity by cigarette smoking could contribute to tobacco-induced cancer, alcohol-induced liver disease, and the risk of acetaminophen hepatotoxicity.