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.

Age-dependent, seasonal and daily variations of the DNA damaging capacity of the hepatocarcinogen ZAMI 1305 in female rat liver.

A single injection of the sex-dependent hepatocarcinogen DL-1-(2-nitro-3-methyl-phenoxy)-3-tert-butylamino-propan-2-ol (ZAMI 1305) caused age-related DNA damage, as evaluated by alkaline sucrose gradient analysis, in the liver of female Wistar rats. DNA damage reached a maximum at 4-6 weeks of age, about the onset of sexual maturity, and decreased thereafter. In young rats (5-8 weeks of age), the amount of ZAMI 1305-induced DNA damage showed seasonal and daily differences, being higher when the molecule was administered in winter in respect to summer and in the evening in respect to the morning. In older rats (15-22 weeks of age), no seasonal and daily variations were observed.

Thyroid and chemical hepatocarcinogenesis: further insights from the hepatocarcinogen ZAMI 1305.

The beta-blocker DL-1-(2-nitro-3-methyl-phenoxy)-3-tert-butylaminopropan-2-ol (ZAMI 1305), oncogenic to the liver of the female but not of the male Wistar rat, was used to investigate some aspects of the relationship between liver and thyroid during chemical hepatocarcinogenesis. Thyroidectomy (TDX) strongly reduces the amount of hepatic DNA damage induced by a single administration of ZAMI 1305 in the female Wistar rat. One week of treatment with triiodothyronine (T3) completely restores the susceptibility of the liver of thyroidectomized animals to the genotoxic activity of the molecule. The amount of hepatic DNA damage in intact females varies with the age of the animal, being maximal in rats of 4-8 weeks of age, when T3 serum concentration are also maximal. An increase of relative thyroid weight, coupled with histological hyperplasia of the gland, is observed in female Wistar rats treated for 6 months with ZAMI 1305. Minimal changes of the thyroid are observed in ZAMI 1305-treated male rats. The increase of relative thyroid weight in female rats appears to be related to the severity of preneoplastic and neoplastic liver changes. These findings and several suggestions from the literature lead us to propose a model for the interaction between liver and thyroid during chemical hepatocarcinogenesis.