Polymorphism of a gene that metabolize chemical substance, biological monitoring and health effect

化学物质代谢基因多态性、生物监测及健康效应

• 批准号: 10670323
• 负责人: NAKASHIMA Hiroshi
• 金额: $ 2.05万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670323/
• 关键词: mollecular epidenmiology; polymorphism; organic solvent; metabolism; health effect

Cytocrome P450 2E1 (CYP2E1) is enrolled to metabolism of chemical substances. Promoter region of CYP2E1 is polymorphic, namely genotype 1/1, 1/2 and 2/2. Expression level becomes higher in that order. In this study, we investigated relationship between CYP2E1 genotype and metabolism or health effect through the study of dimethylformamide (DMF), which is toxic to liver, absorbed through Skin.Metabolism Eleven volunteers were exposed to DMF and the biological half-life (BHL) of n-monomthylformamide (NMF), which is the metabolite of DMF, was examined. Especially when DMF was absorbed through skin, BHL showed stepwise decrease (4.7±1.4 hours for 1/1 type (n=7), 3.9±0.5 hours for 1/2 type (n=3) and 3.1 hours for 2/2 type (n=1)). But, it was difficult to say conclusive thing for its small sample size. We exposed two new 1/2 type volunteers to DMF. Analysis including the result of two new volunteer is now under way.Dimethylacetoamide (DMAc) is also metabolized by CYP2E1. Because we have the volunteer exposure experiment data of DMAc, we examined the genotype of volunteers. We failed to analize the relationship of CYP2E1 genotype and DMAc metabolism, because all of volunteers was 1/1 type.Health effect Cross-sectional study was done in the factory where people handle with DMF. We planned to examine two things. 1) Is there any adverse health effect due toDMF? 2) Does genotype of CYP2E1 affect the result, if we observed adverse health effect? Attention was specially paid to hepatic or neuronal function (both central and peripheral nervous system). Some items on subjective symptom or objective examination such as clinical chemistry showed tentative positive result, but we could not observe positive relationship after adjustment of confounding factors. In the factory we studied, no clear-cut adverse health effect was observed. Therefore, no modification by CYP2E1

Cytocrome P450 2 E1（CYP 2 E1）入组化学物质代谢。CYP 2 E1基因启动子区具有多态性，即基因型1/1、1/2和2/2。表达水平以该顺序变得更高。本研究通过对二甲基甲酰胺（DMF）代谢的研究，探讨CYP 2 E1基因型与DMF代谢或健康效应的关系。代谢11名志愿者暴露于DMF，测定DMF代谢产物N-单甲基甲酰胺（NMF）的生物半衰期。特别是当DMF经皮肤吸收时，BHL呈阶梯式下降（1/1型（n=7）为4.7±1.4小时，1/2型（n=3）为3.9±0.5小时，2/2型（n=1）为3.1小时）。但是，由于样本量小，很难说是决定性的。我们将两名新的1/2型志愿者暴露于DMF。包括两名新志愿者的结果在内的分析正在进行中。二甲基乙酰胺（DMAc）也通过CYP 2 E1代谢。由于我们有DMAc的志愿者暴露实验数据，我们对志愿者的基因型进行了检测。由于受试者均为1/1型，故未能分析CYP 2 E1基因型与DMAc代谢的关系。我们计划检查两件事。1)DMF是否会对健康产生不良影响？2)如果我们观察到不利的健康影响，CYP 2 E1基因型是否会影响结果？特别注意肝脏或神经元功能（中枢和外周神经系统）。主观症状或客观检查中的某些项目如临床化学呈初步阳性结果，但在调整混杂因素后未观察到阳性关系。在我们研究的工厂中，没有观察到明显的不良健康影响。因此，CYP 2 E1未进行修饰