Evaluation of flutamide genotoxicity in rats and in primary human hepatocytes

Flutamide, an effective competitive inhibitor of the androgen receptor used orally for palliative treatment of prostatic carcinoma and regulation of p rostatic hyperplasia was evaluated for its genotoxic effects in the intact rat and in primary cultures of human hepatocytes. Negative responses were o btained 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 initiat ing agent at the dose of 500 mg/kg/week for 6 successive weeks, gamma-gluta myltraspeptidase-positive foci were detected only in 3 of 10 rats. There wa s no evidence of a promoting effect on the development of aberrant crypt fo ci in rats given 100 mg/kg flutamide on alternate days for 8 successive wee ks. In primary cultures of human hepatocytes from one male and one female d onor DNA fragmentation as measured by the Comet assays, and DNA repair synt hesis as revealed by quantitative autoradiography, were absent after a 20 h r exposure to flutamide concentrations ranging from 18 to 56 mu M. Taken as a whole, our results seem to indicate that flutamide is a non-genotoxic dr ug.