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Genotoxicity and carcinogenicity studies of soy isoflavones
R R Misra1, S D Hursting, S N Perkins
1Office of Preventive Oncology, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland, USA.
Abstract:
The potential cancer preventive efficacy of soy isoflavones is being investigated in preclinical and phase 1 clinical studies sponsored by the U.S. National Cancer Institute. Although 90-day oral toxicity studies with PTI G-2535 (an investigational soy isoflavone drug product) in rats and dogs, as well as teratology studies, indicated no signs of toxicity, there remains a mechanistic concern associated with the ability of isoflavones (i.e., genistein) to inhibit topoisomerase, possibly leading to DNA strand breaks. The present report describes results from two in vitro genotoxicity studies, one in vivo genotoxicity study, and a single carcinogenicity study conducted in p53 knockout mice. Bacterial mutagenesis experiments using six tester strains without metabolic activation revealed no evidence that PTI G-2535 was mutagenic. In similar experiments with exogenous metabolic activation there were statistically significant increases in revertants, but less than twofold, in a single (Salmonella typhimurium TA100) tester strain. Mouse lymphoma cell mutagenesis experiments conducted with and without metabolic activation revealed statistically significant increases in mutation frequency at PTI G-2535 concentrations > or = 0.8 and 12 microg/ml, respectively; such increases were dose related and increases in the frequency of both small and large colonies were observed. A statistically significant increase in the frequency of micronucleated polychromatic erythrocytes was also seen 24 hours after treatment in male, but not female, mice who received 500 and 1000 mg/kg body weight PTI G-2535; however,such increases were small, were not dose related, and were not observed 48 hours after treatment. In contrast, dietary genistein had no effect on survival, weight gain, or the incidence or types of tumors that developed in cancer-prone rodents lacking the p53 tumor suppressor gene, p53 knockout mice. The apparent risk/benefit of isoflavone ingestion may ultimately depend on the dose and developmental timing of exposure.
Insights
Soy isoflavones (PTI G-2535) showed mixed genotoxicity results in lab tests, with some mutagenic potential but no carcinogenic effect in p53 knockout mice. Further research is needed on risk and benefit based on dose and timing.
Area of Science:
- Biochemistry
- Toxicology
- Cancer Research
Background:
- Soy isoflavones are investigated for cancer prevention.
- Mechanistic concerns exist regarding isoflavone inhibition of topoisomerase and potential DNA damage.
- PTI G-2535 is an investigational soy isoflavone drug product.
Purpose of the Study:
- To evaluate the genotoxicity and carcinogenicity of PTI G-2535.
- To assess the potential DNA damaging effects of soy isoflavones.
Main Methods:
- In vitro bacterial mutagenesis assays (Salmonella typhimurium).
- In vitro mouse lymphoma cell mutagenesis assays.
- In vivo genotoxicity assay (micronucleated erythrocytes in mice).
- Carcinogenicity study in p53 knockout mice.
Main Results:
- No mutagenicity observed in bacterial assays without metabolic activation.
- Slight mutagenicity observed in Salmonella typhimurium TA100 with metabolic activation.
- Dose-related increases in mutation frequency observed in mouse lymphoma cells.
- Transient, small increases in micronucleated erythrocytes in male mice at high doses.
- No effect on tumor incidence in p53 knockout mice fed genistein.
Conclusions:
- PTI G-2535 exhibits some in vitro genotoxic potential, but not in all assays.
- No evidence of carcinogenicity was found in p53 knockout mice.
- The risk/benefit of soy isoflavone exposure may depend on dose and timing.