Martelli A, Campart G B, Carrozzino R, Ghia M, Mattioli F, Mereto E, Orsi P, Puglia C P
Department of Internal Medicine, University of Genova, Italy.
Pharmacol Toxicol. 2000 Mar;86(3):129-34. doi: 10.1034/j.1600-0773.2000.d01-24.x.
Flutamide, an effective competitive inhibitor of the androgen receptor used orally for palliative treatment of prostatic carcinoma and regulation of prostatic hyperplasia was evaluated for its genotoxic effects in the intact rat and in primary cultures of human hepatocytes. Negative responses were obtained in all the in vivo assays as well as in the in vitro assay. In rats given a single oral dose of 500 mg/kg flutamide, fragmentation and repair of liver DNA were absent, and no increase was observed in the frequency of micronucleated hepatocytes. In the liver of rats given flutamide as initiating agent at the dose of 500 mg/kg/week for 6 successive weeks, gamma-glutamyltraspeptidase-positive foci were detected only in 3 of 10 rats. There was no evidence of a promoting effect on the development of aberrant crypt foci in rats given 100 mg/kg flutamide on alternate days for 8 successive weeks. In primary cultures of human hepatocytes from one male and one female donor DNA fragmentation as measured by the Comet assays, and DNA repair synthesis as revealed by quantitative autoradiography, were absent after a 20 hr exposure to flutamide concentrations ranging from 18 to 56 microM. Taken as a whole, our results seem to indicate that flutamide is a non-genotoxic drug.
氟他胺是一种有效的雄激素受体竞争性抑制剂，口服用于前列腺癌的姑息治疗和前列腺增生的调节。我们评估了它对完整大鼠和人肝细胞原代培养物的遗传毒性作用。在所有体内试验以及体外试验中均得到阴性结果。给大鼠单次口服500mg/kg氟他胺后，肝脏DNA无断裂和修复情况，微核化肝细胞的频率也未增加。以500mg/kg/周的剂量连续6周给大鼠服用氟他胺作为启动剂，在10只大鼠中仅有3只检测到γ-谷氨酰转肽酶阳性灶。连续8周隔天给大鼠服用100mg/kg氟他胺，没有证据表明其对异常隐窝灶的形成有促进作用。在来自一名男性和一名女性供体的人肝细胞原代培养物中，用彗星试验检测，在暴露于浓度范围为18至56μM的氟他胺20小时后，未出现DNA断裂；用定量放射自显影显示，也未出现DNA修复合成。总体而言，我们的结果似乎表明氟他胺是一种非遗传毒性药物。
