过氧化物酶体增殖物激活受体激动剂类药物的致癌性和致癌机制研究进展  

Progress of carcinogenesis and possible mechanisms of peroxisome proliferator-activated receptor agonists

作　　者：邢立国[1,2] 吴英良[2] 

机构地区：[1]沈阳化工研究院安全评价中心国家沈阳新药安全评价研究中心,辽宁沈阳110021 [2]沈阳药科大学生命科学与生物制药学院,辽宁沈阳110016

出　　处：《中国药理学与毒理学杂志》2014年第3期455-461,共7页Chinese Journal of Pharmacology and Toxicology

基　　金：国家科技重大专项(2013ZX09302304)~~

摘　　要：过氧化物酶体增殖物激活受体(PPAR)是一类由配体激活的核转录因子,参与糖类和脂类代谢、炎症反应、细胞生长和分化等过程,以其为靶点的降脂类及抗糖尿病药物已经被开发。PPAR激动剂对动物有致癌性,如一些贝特类PPARα激动剂、噻唑烷二酮类PPARγ激动剂、开发的PPARα/γ双重激动剂和PPARδ激动剂均可使实验动物发生肿瘤。PPARα激动剂的致癌机制同PPARα受体有关,激活受体调节代谢产生脂类异常,也引起过氧化物酶体氧化酶活性增加,产生活性氧导致DNA的损伤。枯否细胞通过NADPH氧化酶产生活性氧促进肝细胞增殖,抑制凋亡。PPARγ激动剂的致癌性与结石形成有关。PPAR激动剂是否对人具有致癌性尚未证实,临床应用仍有致癌风险。本文主要综述PPAR激动剂致癌性和致癌机制研究进展,希望对该类药物的开发有所帮助。Peroxisome proliferator-activated receptors（ PPARs） are ligand-activated nuclear transcription factors,playing an important role in the regulation of glucose and lipids metabolism,inflammation response,proliferation and differentiation. Some drugs targeted on PPARs,such as lipid-lowering and antidiabetic drugs have been developed. Some PPAR agonists were found carcinogenic in animal experiments,including PPARα agonist fibrates,PPARγ agonist thiazolidinediones,PPARα /γ dual agonist compounds,and PPARδ agonist compounds for clinical development. PPARα agonist carcinogenicity is associated with PPAR receptor activation that regulates lipid metabolism,and leads to lipids abnormalities and increase by peroxisome oxidase in reactive oxygen species（ ROS）,causing DNA damage. Kupffer cells can generate ROS by NADPH oxidase that promotes hepatocyte proliferation and inhibition of apoptosis. PPARγ agonist carcinogenicity is generally caused by bladder stone. The carcinogenicity of PPAR agonists to humans has not been confirmed,but the carcinogenic potential of these drugs cannot be ignored.

关 键 词：过氧化物酶体增殖物激活受体激动剂 毒性作用 致癌物 

分 类 号：R99[医药卫生—毒理学]