Blanck A, Liao D, Gustafsson J A, Hällström I P
Department of Medical Nutrition, Huddinge University Hospital, Sweden.
Carcinogenesis. 1995 Feb;16(2):231-5. doi: 10.1093/carcin/16.2.231.
Sex differentiation of liver functions has been shown to be attenuated in preneoplastic rat liver nodules. The present study was performed to investigate whether nodules from male rats are to some extent withdrawn from the normal growth hormone (GH) regulation of these functions. Male and female Wistar rats were treated according to a modified resistant hepatocyte model (RH-model), with diethylnitrosamine initiation and promotion with intragastric administration of 2-acetylaminofluorene (2-AAF) combined with partial hepatectomy (PH). Eleven months post-initiation male rats were treated with either human (hGH) or bovine growth hormone (bGH) or ovine prolactin (oPRL) by continuous infusion for 1 week. The mRNA expression of a number of genes known to be sex differentiated in liver from adult control rats was compared in nodular and surrounding tissue from nodule-bearing male, female and hormone-treated male rats. The basal mRNA expression of the female-predominant cytochrome P4502C12 (CYP2C12) was increased and the male-predominant CYP2C11 was decreased in liver nodules from male rats compared with the surrounding liver. Expression of the prolactin receptor (PRL-r; female > male) and the steroid 5 alpha-reductase (female > male) genes was decreased in male nodules, whereas no difference was observed with respect to GH-receptor (GH-r; female > male) expression in nodules versus surrounding tissue. Early nodules obtained from males treated according to the original RH-model (dietary 2-AAF, 0.02%) and isolated 2 weeks after completion of the 2-AAF/PH treatment showed significantly lower GH-r mRNA levels than the total liver tissue. In hepatocellular carcinomas from hormonally unmanipulated males 11 months post-initiation the decrease in PRL-r expression was even more pronounced than in the nodules and a significant decrease in GH-r expression was seen. In female nodules the only significant difference with respect to the sex differentiated parameters was a lower 5 alpha-reductase expression than in the surrounding tissue. Continuous infusion of both hGH and bGH feminized the expression of all the sex differentiated genes in male tissues and eliminated the previously detected differences between nodules and surrounding tissue. oPRL also eliminated the differences between nodules and surrounding tissue in males and partly feminized the expression of both the 5 alpha-reductase and the PRL-r genes.(ABSTRACT TRUNCATED AT 400 WORDS)
在大鼠癌前肝结节中，肝功能的性别差异已被证明减弱。本研究旨在调查雄性大鼠的肝结节是否在一定程度上脱离了正常生长激素（GH）对这些功能的调节。将雄性和雌性Wistar大鼠按照改良的抗性肝细胞模型（RH模型）进行处理，用二乙基亚硝胺启动，并通过胃内给予2-乙酰氨基芴（2-AAF）联合部分肝切除术（PH）进行促癌。启动后11个月，对雄性大鼠连续输注1周人（hGH）或牛生长激素（bGH）或羊催乳素（oPRL）。比较了已知在成年对照大鼠肝脏中存在性别差异的一些基因在携带结节的雄性、雌性和激素处理雄性大鼠的结节及周围组织中的mRNA表达。与周围肝脏相比，雄性大鼠肝结节中雌性占优势的细胞色素P4502C12（CYP2C12）的基础mRNA表达增加，而雄性占优势的CYP2C11表达降低。雄性结节中催乳素受体（PRL-r；雌性>雄性）和类固醇5α-还原酶（雌性>雄性）基因的表达降低，而结节与周围组织中生长激素受体（GH-r；雌性>雄性）的表达未观察到差异。根据原始RH模型（饮食中含0.02%的2-AAF）处理的雄性大鼠在2-AAF/PH处理完成后2周分离得到的早期结节，其GH-r mRNA水平显著低于全肝组织。在启动后11个月未进行激素处理的雄性大鼠的肝细胞癌中，PRL-r表达的降低甚至比结节中更明显，且GH-r表达显著降低。在雌性结节中，与性别差异参数相关的唯一显著差异是5α-还原酶表达低于周围组织。连续输注hGH和bGH均使雄性组织中所有性别差异基因的表达女性化，并消除了先前在结节与周围组织之间检测到的差异。oPRL也消除了雄性结节与周围组织之间的差异，并使5α-还原酶和PRL-r基因的表达部分女性化。（摘要截于400字）
