Hemolin is a lepidopteran member of the immunoglobulin superfamily, initially isolated from the giant silkmoth Hyalophora cecropia. Hemolin is also induced by stimulation with microbial cell wall c ...

Synthetic estrogens act as tumor promoters in rat liver. Because estrogen treatment markedly increases the secretion of pituitary prolactin, also shown to be a tumor promoter in rat liver, the possibility of a pituitary influence in estrogen promotion was investigated in Wistar rats. In diethylnitrosamine (DEN)-initiated hypophysectomized (hx) female rats, 24 weeks of ethinyl estradiol (EE) administration (500 microg/kg/d, intraperitoneally) did not increase the number of hepatocyte nodules and did not induce hepatocellular carcinoma (HCC) in a 2-year study. Very few placental forms of glutathione-S-transferase (GST-P)-positive foci were observed at the end of EE administration. Estrogen receptor (ER) messenger RNA (mRNA) levels in hx females were 20% of the levels in intact females. EE administration (range, 160-210 microg/kg/d, subcutaneous release pellets) to DEN-initiated intact males and females increased the number and size of hepatocyte foci. A significant increase in HCC frequency was observed in EE-treated females compared with females receiving sham-release pellets, and the latency period for HCC induction was decreased by EE in both males and females. Inhibition of prolactin (PRL) secretion by bromocriptine (Brc) (ParlodelLAR, slow intramuscular release vehicles) during EE treatment decreased the number of foci without affecting their size and markedly prolonged the latency period in both sexes. EE treatment also significantly increased the expression of c-myc, and c-jun, enhanced the levels of growth hormone receptor (GHr) mRNA in females and the levels of ER mRNA in males and "feminized" the expression of the GH-regulated genes cytochrome P450 (CYP), 2C11, CYP 2C12, and GHr in male liver. Brc administration decreased the mRNA levels of the female-predominant CYP 2C12 in EE-treated males but otherwise had no effects. In conclusion, a decreased promotive effect of EE was obtained by decreasing the PRL levels, indicating that estrogens exert at least part of their promotion effects indirectly, by increasing the levels of pituitary PRL.

Male and female Wistar rats were treated according to a slightly modified resistant hepatocyte model, i.e. initiation with diethylnitrosamine and selection of initiated cells with 2-acetylaminofluorene and partial hepatectomy. Two weeks after selection, rats of each sex received daily subcutaneous injections of either recombinant human growth hormone (2.5 IU/kg) or saline for 6 weeks. No effects on growth of early enzyme-altered liver lesions were recorded. The long-term part of the experiment did not show any differences due to growth hormone treatment in terms of incidence or latency time for development of either malignant liver tumors or kidney tumors. Male rats developed liver tumors more frequently than the female rats whereas a higher incidence of kidney tumors was observed in the female rats. Several different malignancies at other sites were also recorded, with no differences between the groups with or without growth hormone treatment. In conclusion, no modifying effects of human growth hormone administration during the post selection phase of the resistant hepatocyte model could be demonstrated on either tumor promotion or tumor progression.

Cyclosporin A (CsA) and the analogue NVA2-cyclosporin (NVA2-Cs) were administered by daily injections (i.p.) to male Sprague-Dawley rats for 7 days. At the 5 mg/kg dose level a significant increase in the ratio between 5α-reduction and 16α-hydroxylation of 4-androstene-3,17-dione was observed with both compounds. Serum levels of corticosterone were significantly increased in these rats. A daily dose of 50 mg/kg gave rise to more pronounced changes in the metabolism of 4-androstene-3,17-dione, with an almost 10-fold increase in the 5α/16α-ratio and a decrease in 6β-hydroxylation. At the high dose level serum levels of corticosterone increased >2-fold, whereas testosterone decreased. This decrease was more pronounced with CsA treatment (>40-fold) than with NVA2-Cs (>3-fold). A significant decrease in the serum levels of luteinizing hormone (LH) was observed with high dose CsA treatment. High dose CsA and NVA2-Cs reduced serum prolactin levels, 6- and 3.6-fold, respectively. A small but significant increase in the serum level of creatinine was observed only in rats receiving NVA2-Cs, 50 mg/kg. The changes in hepatic steroid-metabolizing enzymes following CsA and NVA2-Cs treatment indicate that both compounds influence male rat liver via neuroendocrine mechanisms previously shown to regulate a number of hepatic functions, including several steroid-metabolizing enzymes. These functions are regulated from the hypothalamus, through the secretory pattern of growth hormone. The observed effects of CsA and NVA2-Cs might be due to an indirect action on growth hormone secretion, where an altered testosterone production exerts an influence at the hypothalamic level, and/or the result of a direct effect on the hypothalamus.