Genetic toxicity studies with genistein

Abstract

Genistein is a phytoestrogen that occurs naturally in the diet especially in soybeans and soy-based foods. Genistein and related phytoestrogens are of interest as chemopreventive agents for a variety of diseases and cancers based on epidemiologic evidence of reduced cancer rates in populations with a high intake of soy. Although soy and its constituents have been consumed at high levels in Asian populations without apparent adverse effects, concern has been raised of potential adverse effects due to estrogenic and other activities of the isoflavones. In these studies, genistein was evaluated for mutagenicity and clastogenicity in vitro in the S. typhimurium assay (Ames Test), the mouse lymphoma assay and in vivo in the micronucleus test in mice and rats. There was no evidence for a mutagenic effect in the in vitro S. typhimurium assay with and without metabolic activation (S9). In the in vitro mouse lymphoma assay, genistein increased resistant mutants with and without metabolic activation (S9), which were predominantly small colonies indicating that genistein acts as a clastogen. Three independent in vivo micronucleus tests were performed in Moro mice, RAIf rats and Wistar rats. MORO male and female mice were treated orally for 14 days at doses up to 20 mg/kg/day. RAIf and Wistar male and female rats were treated orally at doses up to 2000 mg/kg without an increase in micronuclei in treated mice or rats. It is concluded that genistein was not mutagenic in the S. typhimurium assay or mutagenic or clastogenic in vivo in the mouse and rat micronucleus test. In the mouse lymphoma assay, genistein induced an increase of predominantly small colonies indicating that genistein acts as a clastogen. This observation is in agreement with published data on the inhibitory action of genistein on topoisomerase II, which is known to lead to chromosomal damage with a threshold dose response.