Critical role of gonadal hormones on the genotoxic activity of the hepatocarcinogen DL-ZAMI 1305.

The DNA damaging capacity of the sex-dependent hepatocarcinogen beta-blocker DL-1-(2-nitro-3-methyl-phenoxy)-3-tert-butylamino-propan-2-ol (DL-ZAMI 1305) was evaluated in different sex hormonal conditions. A single injection of DL-ZAMI 1305 causes DNA damage in the liver of the female but not the male Wistar rat. When the hormonal environment of the female rat is converted to 'male type' by ovariectomy and 1 week of treatment with testosterone, DNA damage by DL-ZAMI 1305 is completely abolished. On the contrary, in male rats orchiectomy coupled to 17 beta-estradiol administration increases the amount of hepatic DNA damage by DL-ZAMI 1305 to values similar to those observed in intact female rats. DL-ZAMI 1305 induces hepatic DNA damage also when administered to female Sprague-Dawley and Fisher 344 female rats. It is uneffective instead on the male rats of these strains. Moreover, in the female Fisher 344 rat phenobarbital pretreatment reduces the DNA damaging capacity of DL-ZAMI 1305. Our data indicate that the genotoxic activity of DL-ZAMI 1305 depends on the sex-hormonal status of the animal and that this is possibly due to a modulation of the microsomal mixed function oxidase system by sex hormones.