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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 receptor (PPAR) is a type of ligand-activated nuclear transcription factor involved in carbohydrate and lipid metabolism, inflammatory response, cell growth and differentiation processes, with its target of reduction Lipids and anti-diabetic drugs have been developed. PPAR agonists are carcinogenic to animals, such as some fibrates PPARα agonists, thiazolidinedione PPARγ agonists, PPARα / γ dual agonists and PPARδ agonists developed tumors in experimental animals. The oncogenic mechanism of PPARα agonists is related to the PPARα receptor, which activates the receptor to regulate metabolism and produce lipid abnormalities. It also leads to the increase of peroxisomal oxidase activity and the production of reactive oxygen species which lead to DNA damage. Kupffer cells produce reactive oxygen species through NADPH oxidase to promote hepatocyte proliferation and inhibit apoptosis. Carcinogenicity of PPARγ agonists is associated with stone formation. Whether PPAR agonists are carcinogenic to humans has not been confirmed yet and there is still a carcinogenic risk to clinical application. This article reviews the PPAR agonist carcinogenicity and carcinogenesis research progress, hoping to help the development of such drugs.