Reduction of ENU-induced transversion mutations by the isoflavone genistein in Escherichia coli

In studies of mutagenesis induced by the carcinogen N-ethyl-N-nitrosourea ( ENU) in the bacterium Escherichia coli FX-11, it was observed that G:C to A :T transitions did not require the inducible umuDC gene products, while a p ortion of the A:T to G:C transitions and all transversion mutations were de pendent on a functional umuC gene. This observation suggested that the diff erent base substitutions may result from differential processing of specifi c DNA adducts produced by ENU. To further understand these processes, we ha ve investigated the effect of the soybean isoflavone genistein on the produ ction of ENU-induced mutations. This compound, in particular, has been show n to exhibit numerous effects including the inhibition of the growth or pro liferation of a variety of cancers, inhibition of angiogenesis, inhibition of tyrosine protein kinases and anti-oxidant properties. In our experiments , tyrosine defective (TyrA(-)) E. coli were exposed to ENU and a portion of the ENU-treated cells were exposed to genistein. The results showed a thre e-fold reduction in the overall mutation frequency when cells were treated with genistein subsequent to ENU-exposure and this anti-mutagenic effect wa s dependent on the dose of genistein employed. However, only certain types of base substitution mutagenesis were affected. In particular, transversion mutations were reduced an average of about 8.5-fold, while transitions wer e not greatly affected. In addition, UV-mutagenesis was reduced about three -fold and induction of the SOS response (as monitored with a sulA-lacZ fusi on) was decreased. These results suggest that genistein may interfere with expression of the SOS response, including the UmuC-mediated lesion bypass m echanism that is necessary for UV-mutagenesis and the generation of transve rsions by ENU in E. coli. (C) 2001 Elsevier Science B.V. All rights reserve d.