Suppressive effect of oestradiol on chemical hepatocarcinogenesis in rats

Abstract

Aims: To examine the effects of oestradiol and testosterone on the early carcinogenic changes expressed in rat liver from the diethylnitrosamine (DEN), 2-acetylaminofluorene (AAF), partial hepatectomy (PH) model of hepatocarcinogenesis.

Methods: Preneoplastic liver lesions were evaluated using immunohistochemical analysis of glutathione-S-transferase placental form (GST-P) expression; oestrogen and androgen receptor levels were measured by radioimmunoassay.

Results: Oestradiol administration to non-castrated DEN-AAF-PH treated males resulted in a decrease in the area of GST-P positive foci, while testosterone increased the serum oestradiol level and reduced the area. In males, castration alone and castration with oestradiol replacement significantly reduced the GST-P positive area, and increased the hepatic oestrogen receptor level. In DEN-AAF-PH treated females, castration with testosterone replacement was associated with a significant increase in the GST-P positive area and the hepatic androgen receptor level.

Conclusion: These findings suggest that exogenous and endogenous oestradiol can suppress chemical hepatocarcinogenesis. It appears that oestrogen receptors may be involved in the inhibition of malignant transformation of preneoplastic liver cells, while androgens and androgen receptors are involved in hepatocarcinogenesis.

Figure 1

Experimental schedule in DEN-AAF-PH treated rats. Control groups (groups 1 and 7, PH control) were subjected to two thirds PH only. Sham operated groups were treated with DEN-AAF-PH without (groups 2 and 8, DEN-AAF-PH) or with sex steroid hormones (oestradiol in group 3, DEN-AAF-PH + oestradiol; testosterone in group 4, DEN-AAF-PH + testosterone). Castrated groups were treated without (groups 5 and 9, castration + DEN-AAF-PH) or with the opposite sex hormone (oestradiol in group 6, castration + DEN-AAF-PH + oestradiol replacement; testosterone in group 10, castration + DEN-AAF-PH + testosterone replacement).

Figure 2

GST-P positive liver foci in non-castrated male rats induced using the DEN-AAF-PH model (A) given oestradiol (B) or testosterone (C). Original magnification × 5.

Figure 3

Effect of castration and opposite sex steroid hormone on the development of GST-P positive liver foci in male and female rats induced using the DEN-AAF-PH model. Original magnification × 5.

Figure 4

Numbers and areas of GST-P positive liver foci in non-castrated male rats induced using the DEN-AAF-PH model with oestradiol or testosterone. *p<0.05 versus corresponding value for DEN-AAF-PH only; †p<0.05 versus corresponding value for DEN-AAF-PH + testosterone (two tailed Mann-Whitney U test). Values are mean (SD).

Figure 5

Areas of GST-P positive liver foci in male and female rats induced in the DEN-AAF-PH model with castration and opposite sex steroid hormone. *p<0.05 versus corresponding value for DEN-AAF-PH only; †p<0.05 versus corresponding value for castration + DEN-AAF-PH (two tailed Mann-Whitney U test). Values are mean (SD).