Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oestrogens and androgens stimulate collagen matrix synthesis, while progesterone is a competitive inhibitor for the 5 alpha-reduction of testosterone to 5 alpha-dihydrotestosterone (DHT). The anti-androgen finasteride is a specific inhibitor of the 5 alpha-reductase type 2 isoenzyme, associated with anabolic functions. The aim of this investigation is to study the effects of progesterone and finasteride on 5 alpha-reduction of androgen substrates by human gingival fibroblasts. Monolayer cultures of human gingival fibroblasts (HGF) of the 4th 9th passage were established in Eagle's minimum essential medium (MEM). Duplicate incubations were performed with 14C-testosterone/14C-4-androstenedione as substrates and progesterone (P) or finasteride (F), at concentrations of 0.5, 1, 3 and 5 microg/ml, alone and in combination, for 24 h. Similarly, the effects of the alkaline phosphatase inhibitor levamisole (L, 30 microg/ml) and P were studied. Steroid metabolites were analysed and quantified, using a radioisotope scanner. Progesterone inhibited DHT synthesis in HGF from 14C-testosterone by 24-62% (n = 8; p < 0.01). Finasteride caused 59 82% inhibition (n=8;p<0.01). The combination of P+F showed a similar degree of inhibition (68-78%) of DHT synthesis to that of F alone (n = 8; p<0.01). There was 35-56% stimulation of 17beta-HSD (hydroxysteroid dehydrogenase) activity by P, F and P + F (n = 8; p < 0.01). When 14C-4-androstenedione was used as substrate there was 47% inhibition of 5 alpha-reductase activity at higher concentrations of P and 63 and 44% stimulation at 0.5 and 1 microg/ml (n = 8;p < 0.01). F and P + F caused 40-67% inhibition of this activity. P, F and P + F caused 2-2.7-fold stimulation of 17beta-HSD activity in response to all concentrations studied. L inhibited DHT synthesis from both substrates by 36-38%, with further inhibition of 55-70% (n = 4; p < 0.01), with P; this is suggestive of ligand-independent alkaline phosphatase activity mediated by 5 alpha-reductase. Inhibition of 5 alpha-reductase activity by finasteride in gingival fibroblasts is suggestive of target tissue anabolic functions in gingivae and competitive inhibition by progesterone, is suggestive of regulation of hormone mediated tissue responses during repair.
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PMID:Effects of the anti-androgen finasteride on 5 alpha-reduction of androgens in the presence of progesterone in human gingival fibroblasts: modulatory actions of the alkaline phosphatase inhibitor levamisole. 1098 77

In both sexes, a reduction in sex steroid production with aging impairs the musculoskeletal system. The goal of our study was to test the ability of WH-9062, a novel non-steroidal small molecule inhibitor of the 17beta-Hydroxysteroid Dehydrogenase type 2 enzyme, to maintain or improve bone strength without raising serum levels of testosterone or estradiol. Mature, female cynomolgus monkeys with sealed growth plates were allocated into six groups: Sham controls, OVX controls, OVX+Premarin (15 mg/kg/d), and three groups of OVX monkeys receiving WH-9062 at 1, 5 and 25 mg/kg/day. All treatments were administered by daily oral dosing for 23 weeks. Changes in lipid profile caused by OVX were corrected with WH-9062 and included lowering total of cholesterol and non-HDL cholesterol, and maintenance of initial plasma levels of HDL cholesterol. Only the highest dose of WH-9062 lowered bone resorption relative to OVX controls. Elevated bone specific alkaline phosphatase, osteocalcin, BMC and dynamic bone histomorphometry data resulted in desirable bone balance and bone strength. The obtained results support our theory that inhibition of 17beta-HSD type 2 resulted in high local estrogen and/or testosterone levels leading to maintenance of bone formation and bone strength. Collectively, our data demonstrated that the treatment paradigm that utilizes tissue selectivity and receptor bioavailability in conversion of inactive hormones to active forms could be achieved and could result in desirable effects on target tissues such as bone and muscles.
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PMID:Effect of 17beta-hydroxysteroid dehydrogenase type 2 inhibitor on bone strength in ovariectomized cynomolgus monkeys. 1879 60

Adult virgin 4-day cycling synchronized Charles foster females were treated subcutaneously (0.05 mg/kg body wt/day) with sodium acetate (control), lead acetate or cadmium acetate alone, or both during gestational period, with pretreatment of 5 days prior to mating. There were no alterations in reproductive performance in all metal-treated groups. Implantation enzymes, cathepsin-D and alkaline phosphatase, activity were altered, but no change in the reproductive performance was observed. The key steroidogenic enzymes of ovary and placenta (3beta-HSD and 17beta-HSD), along with gonadal steroids, were affected the most in cadmium and combined treated animals whereas lead-treated animals showed a minimum change compared to the control group. Maximum displacement of zinc bound to metallothionein was more in cadmium and combined treated rats when compared to other metal-treated groups. Biomolecules such as glycogen, protein, RNA, DNA, and protein content were affected in all metal-treated groups, whereas cadmium-treated animals showed greater effect. General parameters of toxicity such as alkaline phosphatase, serum glutamate pyruvate transaminase, and creatinine were altered but were within the normal range. Biochemical effects are correlated with metals accumulated in blood, reproductive tissue such as placenta and ovary.
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PMID:Biochemical effects of gestational coexposure to lead and cadmium on reproductive performance, placenta, and ovary. 1897 98