Fang N, Casida J E
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112, USA.
Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3380-4. doi: 10.1073/pnas.95.7.3380.
Rotenone and rotenoid-containing botanicals, important insecticides and fish poisons, are reported to have anticancer activity in rats and mice. The toxic action of rotenone is attributed to inhibition of NADH:ubiquinone oxidoreductase activity and the purported cancer chemopreventive effect of deguelin analogs has been associated with inhibition of phorbol ester-induced ornithine decarboxylase (ODC) activity. This study defines a possible relationship between these two types of activity important in evaluating the toxicology of rotenoid pesticides and the suitability of the anticancer model. Fractionation of cubé resin (the commercial rotenoid pesticide) establishes that the activity in both assays is due primarily to rotenone (IC50 = 0.8-4 nM), secondarily to deguelin, and in small part to rotenolone and tephrosin. In addition, the potency of 29 rotenoids from cubé insecticide for inhibiting NADH:ubiquinone oxidoreductase in vitro assayed with bovine heart electron transport particles satisfactorily predicts their potency in vivo in the induced ODC assay using noncytotoxic rotenoid concentrations with cultured MCF-7 human breast cancer cells (r = 0.86). Clearly the molecular features of rotenoids essential for inhibiting NADH:ubiquinone oxidoreductase are similar to those for blocking ODC induction. This apparent correlation extends to 11 flavonoids and stilbenoids from cubé resin (r = 0.98) and genistein and resveratrol except for lower potency and less selectivity than the rotenoids relative to cytotoxicity. These findings on cubé insecticide constituents and our earlier study comparing rotenone and pyridaben miticide indicate that inhibition of NADH:ubiquinone oxidoreductase activity lowers the level of induced ODC activity leading to the antiproliferative effect and anticancer action.
鱼藤酮和含鱼藤酮类植物提取物是重要的杀虫剂和鱼毒，据报道在大鼠和小鼠中具有抗癌活性。鱼藤酮的毒性作用归因于对NADH：泛醌氧化还原酶活性的抑制，而鱼藤素类似物所谓的癌症化学预防作用与抑制佛波酯诱导的鸟氨酸脱羧酶（ODC）活性有关。本研究确定了这两种活性之间的可能关系，这对于评估鱼藤酮类农药的毒理学和抗癌模型的适用性很重要。对立方树脂（商业鱼藤酮类农药）进行分级分离表明，两种测定中的活性主要归因于鱼藤酮（IC50 = 0.8 - 4 nM），其次是鱼藤素，还有一小部分归因于鱼藤醇酮和灰叶素。此外，用牛心电子传递颗粒体外测定的来自立方杀虫剂的29种鱼藤酮类化合物抑制NADH：泛醌氧化还原酶的效力，令人满意地预测了它们在使用非细胞毒性鱼藤酮类化合物浓度的培养MCF - 7人乳腺癌细胞的诱导ODC测定中的体内效力（r = 0.86）。显然对于抑制NADH：泛醌氧化还原酶至关重要的鱼藤酮类化合物的分子特征类似于阻断ODC诱导的分子特征。这种明显的相关性扩展到来自立方树脂的11种黄酮类化合物和芪类化合物（r = 0.98）以及染料木黄酮和白藜芦醇，只是相对于细胞毒性而言，其效力较低且选择性不如鱼藤酮类化合物。关于立方杀虫剂成分以及我们早期比较鱼藤酮和哒螨灵杀螨剂的研究结果表明，抑制NADH：泛醌氧化还原酶活性会降低诱导的ODC活性水平，从而导致抗增殖作用和抗癌作用。
