Randerath E, Randerath K, Reddy R, Danna T F, Rao M S, Reddy J K
Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030.
Mutat Res. 1991 Mar;247(1):65-76. doi: 10.1016/0027-5107(91)90034-l.
The mechanisms of the hepatocarcinogenicity of non-mutagenic peroxisome proliferators, i.e. compounds used as hypolipidemic drugs and industrial plasticizers, are not sufficiently understood. To gain more information on the mechanism of their action, the chronic effects of two structurally diverse peroxisome proliferators on rat-liver DNA were investigated by the 32P-postlabeling assay. Male F-344 rats (1.5 month old) were fed ciprofibrate (0.025%) in the diet for 2, 5, 8, and 16 months or Wy-14643 (0.1%) for 18 months. Liver DNA from individual treated animals (3-4 per group) and age-matched controls was analyzed by the nuclease P1/bisphosphate version of the 32P-postlabeling assay. Three distinct types of exposure-related DNA alterations were observed: (i) A significant reduction of the age-dependent accumulation of I-compounds (putative indigenous DNA modifications) (type 1), (ii) adduct-like DNA derivatives induced by the treatments (type 2), and (iii) as yet structurally uncharacterized radiolabeled material occupying substantial areas of DNA adduct maps and accumulating in an exposure time-dependent manner (type 3). DNA from liver tumors generated by these agents displayed only traces of I-compounds, lacked all but one adduct-like derivatives, and had no type 3 alterations. Thus, in contrast to the non-mutagenicity of peroxisome proliferators in short-term assays, chronic administration of these compounds led to DNA alterations that were detectable by 32P-postlabeling assay.
非诱变过氧化物酶体增殖剂（即用作降血脂药物和工业增塑剂的化合物）的肝癌致癌机制尚未得到充分了解。为了获取更多关于其作用机制的信息，通过³²P后标记分析法研究了两种结构不同的过氧化物酶体增殖剂对大鼠肝脏DNA的慢性影响。给1.5月龄的雄性F-344大鼠喂食含环丙贝特（0.025%）的饲料2、5、8和16个月，或喂食Wy-14643（0.1%）18个月。对每组3-4只经处理动物的肝脏DNA以及年龄匹配的对照动物的肝脏DNA，采用³²P后标记分析法的核酸酶P1/二磷酸酯版本进行分析。观察到三种与暴露相关的不同类型的DNA改变：（i）I类化合物（假定的内源性DNA修饰）随年龄增长的积累显著减少（1型），（ii）处理诱导产生的加合物样DNA衍生物（2型），以及（iii）结构尚未明确的放射性标记物质，占据DNA加合物图谱的大片区域，并以与暴露时间相关的方式积累（3型）。这些试剂诱发的肝肿瘤中的DNA仅显示出微量的I类化合物，除一种加合物样衍生物外均不存在，且无3型改变。因此，与过氧化物酶体增殖剂在短期试验中的非诱变性相反，长期给予这些化合物会导致通过³²P后标记分析法可检测到的DNA改变。
