Ilett K F, Castleden W M, Vandongen Y K, Stacey M C, Butler M A, Kadlubar F F
Department of Pharmacology, University of Western Australia, Nedlands.
Clin Pharmacol Ther. 1993 Sep;54(3):317-22. doi: 10.1038/clpt.1993.153.
The hypothesis that cytochrome P450IA2 (CYPIA2) and/or N-acetyltransferase 2 (NAT2) may be involved in the pathogenesis of peripheral arterial disease was investigated in 90 Australian patients with significant disease and 81 matched control subjects. CYPIA2 and NAT2 phenotypes were determined from urinary metabolite patterns after an oral dose of caffeine. NAT2 phenotype was similar (chi 2 = 0.01; p = 0.98) in both atherosclerotic patients (43.3% rapid) and control subjects (42.0% rapid). CYPIA2 metabolism as measured by the median ratio of (1,7-dimethylxanthine + 1,7-dimethyluric acid)/caffeine was significantly induced by smoking in both patients with atherosclerosis (ratio of 6.5 in nonsmokers and 12.4 in smokers; p < 0.05) and control subjects (ratio of 8.2 in nonsmokers and 14.8 in smokers; p < 0.05), but values in atherosclerotic and control nonsmokers and smokers were similar. Probit transformation of the data revealed a trimodal distribution of ratios in control subjects who were nonsmokers, with 5% classified as poor metabolizers (homozygous rapid) and 95% as extensive metabolizers. The distribution of ratios in control subjects who were smokers was unimodal, whereas among the patients with arterial disease, both smokers and nonsmokers exhibited a bimodal pattern with 8.2% to 16% poor metabolizer and 84% to 91.8% extensive metabolizer phenotypes. When data from both nonsmokers and smokers were combined, the overall proportion of subjects who were poor metabolizers was not significantly different (chi 2 = 1.82; p = 0.18) between control subjects (3.8%) and patients with atherosclerosis (10.6%). Thus biotransformation of environmental or dietary aromatic or heterocyclic amines by NAT2 or CYPIA2 is unlikely to have a significant role in the cause or pathogenesis of peripheral arterial disease.
在90名患有严重外周动脉疾病的澳大利亚患者和81名匹配的对照受试者中，研究了细胞色素P450IA2（CYPIA2）和/或N - 乙酰基转移酶2（NAT2）可能参与外周动脉疾病发病机制的假说。口服咖啡因后，根据尿液代谢物模式确定CYPIA2和NAT2表型。在动脉粥样硬化患者（快速代谢者占43.3%）和对照受试者（快速代谢者占42.0%）中，NAT2表型相似（卡方=0.01；p = 0.98）。通过（1,7 - 二甲基黄嘌呤+1,7 - 二甲基尿酸）/咖啡因的中位数比值衡量的CYPIA2代谢，在动脉粥样硬化患者（非吸烟者该比值为6.5，吸烟者为12.4；p < 0.05）和对照受试者（非吸烟者该比值为8.2，吸烟者为14.8；p < 0.05）中均因吸烟而显著诱导，但动脉粥样硬化患者和对照受试者中的非吸烟者和吸烟者的该比值相似。对数据进行概率单位转换后发现，非吸烟对照受试者的比值呈三峰分布，5%被归类为代谢不良者（纯合快速代谢型），95%为广泛代谢者。吸烟对照受试者的比值分布呈单峰，而在动脉疾病患者中，吸烟者和非吸烟者均表现出双峰模式，代谢不良者表型占8.2%至16%，广泛代谢者表型占84%至91.8%。当将非吸烟者和吸烟者的数据合并时，对照受试者（3.8%）和动脉粥样硬化患者（10.6%）中代谢不良者的总体比例无显著差异（卡方=1.82；p = 0.18）。因此，NAT2或CYPIA2对环境或饮食中的芳香族或杂环胺进行生物转化不太可能在外周动脉疾病的病因或发病机制中起重要作用。
