Marchand L L, Wilkinson G R, Wilkens L R
Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu 96813, USA.
Cancer Epidemiol Biomarkers Prev. 1999 Jun;8(6):495-500.
Cytochrome P4502E1 (CYP2E1) is considered to play an important role in the metabolic activation of procarcinogens such as N-nitrosoamines and low molecular weight organic compounds. An RsaI polymorphism is present in the 5'-flanking region of the CYP2E1 gene, which could possibly affect its transcription. However, the relationship between genotype and the phenotypic catalytic activity of the enzyme has not been defined. Also, the effects in humans of specific dietary factors, other than ethanol, which have been shown in animal and in vitro studies to modulate CYP2E1 activity, are unknown. Accordingly, the CYP2E1-mediated metabolism of chlorzoxazone to its 6-hydroxy metabolite was investigated in 50 healthy Japanese of both sexes in Hawaii. The oral clearance of the in vivo probe, the trait measure of CYP2E1 activity, was smaller than that reported in European-Americans. Significantly, after adjustment for age and sex, the oral clearance of chlorzoxazone decreased with the number of variant c2 alleles, and its mean in the c2/c2 genotype (147 ml/min) was statistically lower (P < or = 0.05) than that for either the homozygous wild-type (238 ml/min) or the heterozygote (201 ml/min) genotypes. Stepwise multiple regression analysis indicated that body weight was a major contributor to the interindividual variability in the oral clearance of chlorzoxazone, accounting for 43% of the variance. Consumption of lettuce, broccoli, and black tea explained additional components of the variability (7, 5, and 6%, respectively), as did medication use (3%), age (4%), and CYP2E1 genotype (5%). Overall, 73% of the variance could be accounted for by these variables. Body weight, lettuce, and use of medications were associated with increased CYP2E1 activity, and the other covariates were associated with reduced enzyme function. Because of the role that CYP2E1 plays in procarcinogen activation, especially of N-nitrosamines involved in lung cancer, the identified factors may account in part for observed differences in individual susceptibility to disease and may also have implications for cancer prevention.
细胞色素P4502E1（CYP2E1）被认为在亚硝胺和低分子量有机化合物等前致癌物的代谢激活过程中发挥重要作用。CYP2E1基因的5'侧翼区域存在一种RsaI多态性，这可能会影响其转录。然而，基因型与该酶的表型催化活性之间的关系尚未明确。此外，除乙醇外，特定饮食因素在动物和体外研究中已显示可调节CYP2E1活性，但对人类的影响尚不清楚。因此，在夏威夷的50名健康日本男女中，研究了CYP2E1介导的氯唑沙宗代谢为其6-羟基代谢物的过程。体内探针的口服清除率是CYP2E1活性的特征性指标，低于欧美人群的报道值。值得注意的是，在对年龄和性别进行校正后，氯唑沙宗的口服清除率随变异c2等位基因数量的增加而降低；其在c2/c2基因型中的平均值（147 ml/min）在统计学上低于纯合野生型（238 ml/min）或杂合子（201 ml/min）基因型（P≤0.05）。逐步多元回归分析表明，体重是氯唑沙宗口服清除率个体间差异的主要影响因素，占方差的43%。生菜、西兰花和红茶的摄入量分别解释了另外7%、5%和6%的差异，药物使用（3%）、年龄（4%）和CYP2E1基因型（5%）也有类似作用。总体而言，这些变量可解释73%的方差。体重、生菜和药物使用与CYP2E1活性增加有关，其他协变量与酶功能降低有关。由于CYP2E1在致癌物激活中所起的作用，尤其是与肺癌相关的亚硝胺的激活，所确定的因素可能部分解释了个体对疾病易感性的差异，也可能对癌症预防具有重要意义。
