Richardson F C, Copple D M, Eacho P I
Toxicology Research Laboratories, Eli Lilly and Co., Greenfield, IN 46140.
Carcinogenesis. 1992 Dec;13(12):2453-7. doi: 10.1093/carcin/13.12.2453.
The effects of the antihistamine methapyrilene (MP) on DNA synthesis in rats and mice were investigated. Previous studies have demonstrated a dose response for tumor induction in the rat but no carcinogenic effect in the mouse. To study the role of DNA synthesis in MP carcinogenesis, rats and mice were administered MP at doses of 0, 62.5, 125, 250 or 1000 p.p.m. in the diet for a period of 1-12 weeks. Bromodeoxyuridine was administered continuously using an osmotic minipump during the last week of treatment to provide an index of DNA synthesis. Results demonstrated that in the rat 250 and 1000 p.p.m. MP increased DNA synthesis in a dose-dependent manner that correlated with the tumor response in previous oncogenic studies. MP at 62.5 p.p.m. did not increase DNA synthesis, indicating a no effect level for cell proliferation and suggesting a no effect level for carcinogenicity by this compound in the rat. MP did not induce DNA synthesis in mice after exposure to 1000 p.p.m. for 12 weeks, nor did it induce changes in serum chemistries or liver histopathology suggestive of overt toxicity as was seen in the rat at 1000 p.p.m. The correlations between labeling index and tumorigenicity in the rat and mouse strongly support a role of cell proliferation in the carcinogenic mechanism of MP.
研究了抗组胺药甲吡那敏（MP）对大鼠和小鼠DNA合成的影响。先前的研究已证明大鼠存在肿瘤诱导的剂量反应，但在小鼠中未发现致癌作用。为了研究DNA合成在MP致癌过程中的作用，给大鼠和小鼠喂食含0、62.5、125、250或1000 ppm MP的饲料，持续1至12周。在治疗的最后一周，使用渗透微型泵持续给予溴脱氧尿苷，以提供DNA合成的指标。结果表明，在大鼠中，250和1000 ppm的MP以剂量依赖性方式增加DNA合成，这与先前致癌研究中的肿瘤反应相关。62.5 ppm的MP未增加DNA合成，表明该化合物对大鼠细胞增殖无影响水平，也提示对大鼠致癌性无影响水平。在小鼠中，暴露于1000 ppm 12周后，MP未诱导DNA合成，也未诱导血清化学或肝脏组织病理学变化，而在大鼠中，1000 ppm时可见明显毒性。大鼠和小鼠中标记指数与致瘤性之间的相关性有力地支持了细胞增殖在MP致癌机制中的作用。
