Gibson G G
School of Biological Sciences, University of Surrey, Guildford, UK.
Toxicol Lett. 1993 May;68(1-2):193-201. doi: 10.1016/0378-4274(93)90130-p.
Peroxisome proliferators are a structurally diverse group of chemicals. They include fibrate hypolipidaemic drugs, phthalate ester plasticisers, phenoxy acid herbicides, azole antifungal drugs, and perflurinated fatty acids. This presentation will focus on the common pleiotropic responses produced by these compounds including hepatomegaly (hyperplasia and hypertrophy), activation of cell cycle S-phase ploidy changes, cytochrome P4504A1 induction, morphometric/biochemical analysis of peroxisome proliferation and stimulation of growth factors, and oncogene activation. Consideration will also be given to the role of recently described Peroxisome Proliferator Activated Receptor in these diverse hepatic responses. Peroxisome proliferators are uniformly negative in a wide range of genotoxicity tests, but nevertheless are complete carcinogens, particularly in rodent liver. Mechanisms of nonmutagenic carcinogenesis will be discussed including the active oxygen hypothesis involving 8-hydroxydeoxyguanosine adducts and the possibility of peroxisome proliferators promoting preexisting lesions by clonal expansion, eventually resulting in frank tumorigenesis. Finally, a consideration of the risk assessment of peroxisome proliferation to humans will be discussed.
过氧化物酶体增殖剂是一类结构多样的化学物质。它们包括贝特类降血脂药物、邻苯二甲酸酯增塑剂、苯氧羧酸类除草剂、唑类抗真菌药物以及全氟脂肪酸。本报告将重点关注这些化合物产生的常见多效性反应，包括肝肿大（增生和肥大）、细胞周期S期倍性变化的激活、细胞色素P4504A1的诱导、过氧化物酶体增殖的形态计量学/生化分析以及生长因子的刺激，还有癌基因激活。还将考虑最近描述的过氧化物酶体增殖物激活受体在这些不同肝脏反应中的作用。过氧化物酶体增殖剂在广泛的遗传毒性试验中均呈阴性，但却是完全致癌物，尤其是在啮齿动物肝脏中。将讨论非诱变致癌的机制，包括涉及8-羟基脱氧鸟苷加合物的活性氧假说以及过氧化物酶体增殖剂通过克隆扩增促进预先存在的病变，最终导致明显肿瘤发生的可能性。最后，将讨论过氧化物酶体增殖对人类风险评估的考量。
