Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Numerous studies have indicated that progesterone metabolites, particularly 3alpha,5alpha-tetrahydroprogesterone, can potently influence multiple brain functions, e.g. they have the capacity to mediate gonadotropin regulation and various anticonvulsive, anesthetic and anxiolytic effects. These circulating progesterone metabolites are likely to represent only a fraction of the bioavailable pool of these steroids in that the central nervous system (CNS) also possesses enzymes that can synthesize these metabolites in situ. Therefore, because the ability of the CNS to produce these neuroactive progestins is an important consideration when assessing overall progestin function and metabolism, we measured the major progesterone metabolizing enzyme activities, namely the cytosolic NADPH and particulate NADH 5alpha-dihydroprogesterone 3alpha-hydroxysteroid oxidoreductase (3alpha-HSOR) and progesterone 5alpha-reductase activities in nine brain regions from random cycling and ovariectomized rats. These assays entailed the use of reverse isotopic dilution analysis and revealed that all three enzymic activities were present in each of the brain regions examined, but that these regions displayed differential patterns with regard to their levels of cytosolic and particulate 3alpha-HSOR activity. The cytosolic 3alpha-HSOR activity was highest in the olfactory bulb/tubercle and colliculi regions which were greater than levels in the hypothalamus/preoptic area and cerebellum which were greater than levels in the amygdala/striatum and hippocampus/dentate gyrus. Midbrain/thalamus, cerebral cortex and pons/medulla were different only from the olfactory bulb/tubercle and colliculi regions. The particulate 3alpha-HSOR activity was highest in the olfactory bulb/tubercle region followed by colliculi, hippocampus/dentate gyrus and pons/medulla which were greater than levels in the hypothalamus/preoptic area, cerebellum and amygdala/striatum. Cerebral cortex and midbrain/thalamus were different only from the olfactory bulb/tubercle area. The highest levels of 5alpha-reductase activity were found in the pons/medulla region followed by the colliculi, midbrain/thalamus, cerebellum and olfactory bulb/tubercle which were greater than levels in the amygdala/striatum, hippocampus/dentate gyrus, hypothalamus/preoptic area and cerebral cortex. It is interesting to note that although 5alpha-reductase may control, at least in part, substrate levels for the 3alpha-HSORs, the distribution of 5alpha-reductase activity in these nine brain regions did not correlate with 3alpha-HSOR levels. The differences in the levels of activity of these three enzymes in various brain regions suggests a role in maintaining a differential balance of the neuroactive steroid, 3alpha,5alpha-tetrahydroprogesterone, and its precursor, 5alpha-dihydroprogesterone, in various regions of the CNS.
J Steroid Biochem Mol Biol 1997 Mar
PMID:Regional distribution of cytosolic and particulate 5alpha-dihydroprogesterone 3alpha-hydroxysteroid oxidoreductases in female rat brain. 921 22

Alterations of steroid hormone biosynthesis and metabolism are suspected to be involved in the pathogenesis of several diseases. Several polymorphisms of the enzymes involved in these processes have already been described and some could be associated with certain diseases. We attempted to examine the sequence variants of these genes in order to find novel variants by an in silico analysis. We analyzed the known human nucleotide sequences of the enzymes p450 side-chain cleavage enzyme, steroid 17-alpha-hydroxylase/17,20-lyase, 3-beta-hydroxysteroid dehydrogenase types 1 and 2, 21-hydroxylase, 11-beta-hydroxylase, aldosterone synthase, aromatase, 11-beta-hydroxysteroid dehydrogenase types 1 and 2, steroid 5-alpha-reductase types 1 and 2, steroid 5-beta-reductase, dehydroepiandrosterone sulfotransferase, 17-beta-hydroxysteroid dehydrogenase types 1-3. The analysis was performed using the National Center for Biotechnology Information Database by the search tool blastn. We found numerous sequence variants in both coding and non-coding sequences. The majority of these sequence variants have already been described, nevertheless, some appear as novel variants. Some of these may also have functional significance. We hypothesize over the possible significance of these findings and briefly review the available literature.
J Steroid Biochem Mol Biol 2002 Nov
PMID:Genomics of steroid hormones: in silico analysis of nucleotide sequence variants (polymorphisms) of the enzymes involved in the biosynthesis and metabolism of steroid hormones. 1258 43

Recent evidence indicates that progesterone metabolites play important roles in regulating breast cancer. Previous studies have shown that breast carcinoma and tumorigenic breast cell lines have higher 5alpha-reductase and lower 3alpha-hydroxysteroid oxidoreductase (3alpha-HSO) and 20alpha-HSO activities and mRNA expression levels than normal tissue and non-tumorigenic cell lines. The 5alpha-reduced progesterone metabolites such as 5alpha-dihydroprogesterone (5alphaP) promote both mitogenic and metastatic activity in breast cell lines in culture, whereas the 4-pregnene metabolites, 4-pregnen-3alpha-ol-20-one (3alphaHP) and 4-pregnen-20alpha-ol-3-one (20alphaHP) have the opposite (anti-cancer-like) effects. The 5alpha-reductase inhibitor dutasteride has been shown to inhibit 5alpha-reduction of testosterone to 5alpha-dihydrotestosterone in prostate tissue, resulting in decreased prostate volume. The aim of this study was to determine if dutasteride is an effective inhibitor of progesterone 5alpha-reduction in human breast cell lines and if such inhibition reduces mammary cell proliferation and detachment. The effect of dutasteride on progesterone metabolizing enzyme activities and mRNA expression were examined in tumorigenic MCF-7 and non-tumorigenic MCF-10A human breast cell lines. Dutasteride (10(-6)M) inhibited progesterone conversion to 5alpha-pregnanes by >95% and increased 4-pregnene production. The results indicated that effects of dutasteride on the progesterone metabolizing enzymes are due to direct inhibition of 5alpha-reductase activity and to altered levels of expression of 5alpha-reductase and HSO mRNAs. Treatment of cells with progesterone without medium change for 72 h resulted in significant conversion to 5alpha-pregnanes and increases in cell proliferation and detachment. The increases in proliferation and detachment were blocked by dutasteride and were reinstated by concomitant treatment with 5alphaP, providing proof-of-principle that the effects were due not to progesterone but to the 5alpha-reduced metabolites. This study provides the first evidence that dutasteride is a potent progesterone 5alpha-reductase inhibitor and that such inhibition may be beneficial in breast cancer.
J Steroid Biochem Mol Biol 2006 Aug
PMID:Dutasteride affects progesterone metabolizing enzyme activity/expression in human breast cell lines resulting in suppression of cell proliferation and detachment. 1680 4