Adult male rodents have a pulsatile profile of growth hormone (GH) release, whereas female rodents have a relatively steady-state pattern with uniform, albeit lower levels of GH. The expression of a number of sexually differentiated hepatic proteins is primarily determined by these plasma GH profiles and only secondarily regulated by gonadal hormones. An important subset of these sexually dimorphic proteins is cytochrome P450s. CYP3A10/6-hydroxylase is a cytochrome P450 that catalyzes the 6-hydroxylation of lithocholic acid. CYP3A10/6-hydroxylase is expressed only in male hamsters; however, mimicking the male GH secretion pattern in females induces expression of the gene to male levels. Using chimeric CYP3A10/6-hydroxylase promoter/luciferase reporter genes transfected into hamster primary hepatocytes, we have shown a GHmediated induction of promoter activity. A combination of 5-deletion constructs, heterologous promoter constructs, and specific mutagenesis was used to localize the DNA element involved in the GH-mediated regulation of CYP3A10/6-hydroxylase promoter activity, which resembles a STAT binding site. Footprint and gel shift analyses confirmed that the expression of the protein binding to this site is regulated by GH and that the DNA-protein complex can be partially supershifted by anti-STAT-5 antibodies. This protein is 50% more abundant in male than in female hamster livers, is absent in hypophysectomized female livers, and is restored when hypophysectomized females are injected with GH in a manner that masculinizes female hamsters in terms of CYP3A10/6-hydroxylase expression. The system characterized and described here is ideally suited for dissecting the molecular details governing the sexually dimorphic expression of liver-specific genes.The expression of a number of sexually differentiated hepatic proteins is primarily determined by plasma growth hormone (GH) profiles and only secondarily regulated by gonadal hormones through their effects on the hypothalamo-pituitary axis and its control of GH secretion (reviewed in references 32, 50, and 46). In rats, gonadal hormones are thought to exert their effects on the liver by two different mechanisms: first by a direct neonatal androgen effect, and second by their effect on the hypothalamus to direct the pattern of GH release from the pituitary. Adult males have a pulsatile profile of GH release, with serum levels becoming undetectable at times and with peaks of 200 to 300 ng/ml, and females have a relatively steadystate pattern of GH release, with uniform, albeit lower levels of serum GH (10 to 20 ng/ml). An important subset of these sexually differentiated hepatic proteins is cytochrome P450s (P450), which are a superfamily of heme-thiolate proteins that metabolize a variety of endogenous and exogenous substrates. They have characteristic, broad but overlapping substrate specificities and perform vital biochemical reactions, including drug detoxification and steroid hormone and bile acid synthesis. More than 220 genes encoding P450s have been f...
The level of expression of a number of sexually differentiated liver proteins is primarily determined by plasma growth hormone (GH). Adult males have a pulsatile profile of GH release, while females have a relatively steady-state pattern of GH release. An important subset of these sexually differentiated hepatic proteins is certain cytochrome P450s (P450s). CYP3A10/6beta-hydroxylase is a male-specific P450 that catalyzes 6beta-hydroxylation of lithocholic acid, and the pattern of GH secretion is directly responsible for male-specific expression of this gene. The DNA element involved in GH-mediated regulation of CYP3A10/6beta-hydroxylase promoter activity binds a member of the STAT (signal transducers and activators of transcription) family of proteins. In this study we functionally demonstrate that two members of the STAT family, STAT 5a and STAT 5b, mediate GH-dependent regulation of CYP3A10/6beta-hydroxylase promoter activity. Furthermore, a neighboring DNA element binds NF-Y, a transcription factor involved in maintaining high levels of transcription of many genes and known to functionally interact with other factors. In the CYP3A10/6beta-hydroxylase gene, NF-Y also modulates binding of STAT 5, thereby modulating GH-mediated activation of its transcription.
The effect of prolonged, oral melatonin treatment on spontaneous mammary tumor development in female C3H/Jax mice was studied. Melatonin was administered at a dose of 25 micrograms/mouse/day from 21 to 44 days of age and 50 micrograms/mouse/day from day 45 onwards. By the age of 12 months, 62.5% of control animals developed tumors as opposed to 23.1% in the melatonin treated group (P less than 0.02). In both control and treated mice, the thoracic pairs of mammary glands were obviously more susceptible to spontaneous mammary tumor development, as at least 50% of the total tumors developed in this region. Reduction in submaxillary and pituitary gland weights of treated animals was observed at necropsy (P less than 0.001). Decreased serum 17-beta-estradiol (E2) levels in melatonin treated mice (P less than 0.05) and a marked reduction in [3H]thymidine incorporation into DNA of melatonin-treated mammary glands (P less than 0.02) positively correlated with the sparse mammary gland development seen in these mice. These observations indicate that at the given dose level, melatonin modulates the degree of development of the mammary epithelium, subsequently reducing spontaneous mammary tumor incidence in these high risk mice.
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