CYP2E1在糖尿病对丙烯腈毒性易感性改变中的作用及其机制

Diabetes mellitus is a metabolic disorder principally characterized by microvascular and macrovascular complications. People with diabetes are more vulnerable to environmental toxicants than the healthy people. The cardiovascular damage, nerve damage as well as liver and kidney injury of environmental toxicants on diabetes are more hazardous than that of healthy people. Currently, the study on the effect and mechanism of the susceptibility of People with diabetes to nvironmental toxicants is an important task of protecting the diabetes. An increased CYP2E1 expression was found in people with diabetes, However, Upregulation of CYP2E1 was able to enhance toxicity of most environmental chemicals. The previous studies indicated that higher expression of Cytochrome P450 2E1 ((CYP2E1) increases the acute neurotoxicity of Acrylonitrile as seen from the accelerated speeds of AN and the increased content of metabolites (CN-). Acrylonitrile, an organic nitrile with neurotoxicty, is widely used in the manufacturing of fibers, plastics and pharmaceuticals. In the further inverstigation, using CYP2E1 inhibitors and antioxidants pretreated on the diabetic rats/mice and IR-cell which were exposed by acrylonitrile to evaluate the role of CYP2E1 in the susceptibility to the toxicity of diabetic rats exposed to acrylonitrile and study its action mechanism. the project is also to evaluate the effects of CYP2E1 inhibitors and antioxidants on the expression of CPYP2E1 and oxidative stress in diabetic rats which exposed to acrylonitrile. The project will provide a scientific basis for formulating health protection policy and hygienic standard for patients with diabetes.

糖尿病是一种内分泌功能紊乱的慢性疾病并可继发多种并发症。糖尿病人群是受环境毒物危害的敏感人群之一，环境毒物对糖尿病人群的心血管、神经的损害及肝、肾的损伤都比健康人群更严重，因此，研究糖尿病对环境毒物毒性的易感性及其作用机制是保护糖尿病患者这一易感人群的重要任务。糖尿病可上调细胞色素P4502E1(CYP2E1)活性，而CYP2E1上调又能使多数环境毒物毒性增强,前期研究发现CYP2E1上调可导致丙烯腈代谢速度加快，代谢产物CN-含量增加，使丙烯腈急性毒性更强。丙烯腈是一种具有挥发性和高毒性的有机腈，应用极为广泛。本项目将采用CYP2E1抑制剂和抗氧化剂对丙烯腈染毒的糖尿病大鼠/小鼠和胰岛素抵抗肝细胞进行预处理，研究糖尿病对以丙烯腈为代表的环境毒物急性毒性易感性的改变特征，探明CYP2E1在糖尿病对丙烯腈急性毒性易感性改变中的作用机制，为制定糖尿病人群的健康防护政策和卫生标准提供科学依据。

糖尿病是一种内分泌功能紊乱的慢性疾病并可继发多种并发症。糖尿病人群是受环境毒物危害的敏感人群之一，环境毒物对糖尿病人群的心血管、神经系统的损害及肝、肾损伤都比健康人群更严重，因此为保护糖尿病这一敏感人群，迫切需要研究糖尿病对环境毒物的易感性及其作用机制。本项目以链脲佐菌素（STZ）诱导型糖尿病大鼠（胰岛素依赖型）和db/db自发性糖尿病小鼠（非胰岛素依赖型）为动物模型，探索糖尿病对工业毒物丙烯腈和饮用水消毒副产物二氯乙腈（亚）急性毒性的易感性及其机制。研究发现STZ诱导型糖尿病和db/db自发性糖尿病均能增强丙烯腈的急性毒性，但这两种类型糖尿病的易感机制不同：STZ诱导型糖尿病通过上调细胞色素P450 2E1（CYP2E1），加快丙烯腈代谢物氰根的大量生成，抑制组织中细胞色素c氧化酶活性，从而造成糖尿病大鼠在丙烯腈急性染毒后死亡率升高，增强其急性毒性。与同窝野生型对照小鼠相比，db/db小鼠的CYP2E1活性没有显著变化，这说明db/db自发性糖尿病增强丙烯腈的急性毒性可能不是通过调控CYP2E1活性介导的。二氯乙腈与丙烯腈有着类似的化学结构同属有机腈类物质，虽然糖尿病能增强丙烯腈的神经毒性，但对二氯乙腈的神经毒性却存在耐受效应，表现在相较于非糖尿病大鼠，STZ诱导型糖尿病大鼠对二氯乙腈致自主活动功能减退和抑郁不动状态等神经行为功能障碍均不敏感，脑氧化损伤和线粒体功能障碍的病理进程也更为缓慢，甚至产生耐受效应。在研究了糖尿病增强丙烯腈急性毒性的毒理学机制研究基础上，开展了天然产物神经保护的应用研究，选用的十字花科植物中硫代葡糖糖苷的酶解产物苯乙基异硫氰酸酯（PEITC）可通过抗氧化、抑制CYP2E1活性和逆转组织CcOx活性延长丙烯腈急性染毒STZ诱导型糖尿病大鼠和db/db小鼠生存时间，降低死亡率从而达到拮抗丙烯腈急性毒性的效果。该项目为制定糖尿病人群的特殊防护政策以及丙烯腈和二氯乙腈的卫生标准提供科学依据，对人类健康和经济发展具有重要意义。. 在国内外刊物共发表论文9篇，其中SCI收录3篇，均标注本项目基金号，申请中国发明专利1项，培养研究生4人（1人已毕业）。