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1: J Steroid Biochem Mol Biol. 2002 Oct;82(2-3):233-9. Related Articles, Links

 

 

Inhibition of type 1 and type 2 5alpha-reductase activity by free fatty acids, active ingredients of Permixon.

Raynaud JP, Cousse H, Martin PM.

 

D.R.I.T.T., Universite Pierre et Marie Curie, 4 Place Jussieu, Paris, France. [email protected]

 

In different cell systems, the lipido-sterolic extract of Serenoa repens (LSESr, Permixon inhibits both type 1 and type 2 5alpha-reductase activity (5alphaR1 and 5alphaR2). LSESr is mainly constituted of fatty acids (90+/-5%) essentially as free fatty acids (80%). Among these free fatty acids, the main components are oleic and lauric acids which represent 65% and linoleic and myristic acids 15%.To evaluate the inhibitory effect of the different components of LSESr on 5alphaR1 or 5alphaR2 activity, the corresponding type 1 and type 2 human genes have been cloned and expressed in the bacxxxvirus-directed insect cell expression system Sf9. The cells were incubated at pH 5.5 (5alphaR2) and pH 7.4 (5alphaR1) with 1 or 3nM testosterone in presence or absence of various concentrations of LSESr or of its different components. Dihydrotestosterone formation was measured with an automatic system combining HPLC and an on-line radiodetector.The inhibition of 5alphaR1 and 5alphaR2 activity was only observed with free fatty acids: esterified fatty acids, alcohols as well as sterols assayed were inactive. A specificity of the fatty acids in 5alphaR1 or 5alphaR2 inhibition has been found. Long unsaturated chains (oleic and linolenic) were active (IC(50)=4+/-2 and 13+/-3 microg/ml, respectively) on 5alphaR1 but to a much lesser extent (IC(50)>100 and 35+/-21 microg/ml, respectively) on 5alphaR2. Palmitic and stearic acids were inactive on the two isoforms. Lauric acid was active on 5alphaR1 (IC(50)=17+/-3 microg/ml) and 5alphaR2 (IC(50)=19+/-9 microg/ml). The inhibitory activity of myristic acid was evaluated on 5alphaR2 only and found active on this isoform (IC(50)=4+/-2 microg/ml).The dual inhibitory activity of LSESr on 5alpha-reductase type 1 and type 2 can be attributed to its high content in free fatty acids.

 

MeSH Terms:

Androgen Antagonists/pharmacology*

Animals

Antilipemic Agents/pharmacology

Cell Line

Cholestenone 5 alpha-Reductase

Fatty Acids, Nonesterified/pharmacology*

Fatty Alcohols/pharmacology

Human

Isoenzymes/antagonists & inhibitors

Isoenzymes/metabolism

Oxidoreductases/antagonists & inhibitors*

Oxidoreductases/metabolism

Plant Extracts/pharmacology*

Sitosterols/pharmacology

Support, Non-U.S. Gov't

Tocopherols/pharmacology

 

Substances:

Androgen Antagonists

Antilipemic Agents

Fatty Acids, Nonesterified

Fatty Alcohols

Isoenzymes

Permixon

Plant Extracts

Sitosterols

Tocopherols

docosanol

sitosterol

Oxidoreductases

Cholestenone 5 alpha-Reductase

 

PMID: 12477490 [PubMed - indexed for MEDLINE]

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scatole cinesi...

 

Mini Rev Med Chem. 2003 May;3(3):225-37. Related Articles, Links

 

 

Steroid 5alpha-reductase inhibitors.

Flores E, Bratoeff E, Cabeza M, Ramirez E, Quiroz A, Heuze I.

 

National University Mexico D.F. and Metropolitan University Mexico D.F., Mexico. [email protected]

 

The objective of this study is to synthesize new steroidal compounds based on the progesterone skeleton with a high inhibitory activity for the enzyme 5alpha-reductase. Presently similar compounds are being used for the treatment of androgen dependent diseases such as: hirsutism, androgenic alopecia, bening prostatic hyperplasia and prostate cancer. Dihydrotestosterone 2 (Fig. (1)), a 5alpha-reduced metabolite of testosterone 1 has been implicated as a causative factor in the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of steroid 5alpha-reductase enzyme. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new antiandrogenic drugs. The advent of finasteride 8 (Fig. (4)) a 5alpha-reductase inhibitor has grately alleviated the symptoms associated with benign prostatic hyperplasia. In our laboratory we recently synthesized several new 16beta-methyl-pregnadiene-3,20-diones derivatives 27 (Fig.(6)), 38-42 (Fig. (11)), 16beta-phenyl-pregnadiene-3,17a-dione derivatives 32-33 (Fig. (7)), 16beta-phenyl-pregnatriene-3,17a-diones, 30, 31 (Fig. (7)) and 16beta-methyl-pregnatriene-3,20-diones 43-46 (Fig. (11)). These compounds were evaluated as 5alpha-reductase inhibitors in the following biological models: Penicillium crustosum broths, the flank organs of gonadectomized male hamsters, the incorporation of radiolabeled sodium acetate into lipids, the effect of the new steroids on the reduction of the weight of the seminal vesicles and on the in vitro metabolism of [(3)H]T to [(3)H]DHT in seminal vesicles homogenates of gonadectomized male hamsters. All trienones 30, 31, and 43-46 in all biological models showed consistently a higher 5alpha-reductase inhibitory activity than the corresponding dienones 27, 32, 33 and 38-42. We believe that with these compounds the 5alpha-reductase enzyme is inactivated by an irreversible Michael type addition of the nucleophilic portion of the enzyme to the conjugated double bond of the steroid. The trienones having a more coplanar structure react faster with the enzyme and thus show a higher inhibitory activity.

 

Publication Types:

Review

Review, Tutorial

 

MeSH Terms:

Androgen Antagonists/pharmacology

Animals

Drug Design

Enzyme Inhibitors/chemical synthesis

Enzyme Inhibitors/chemistry*

Enzyme Inhibitors/pharmacology*

Molecular Structure

Support, Non-U.S. Gov't

Testosterone 5-alpha-Reductase/antagonists & inhibitors*

Testosterone 5-alpha-Reductase/metabolism

 

Substances:

Androgen Antagonists

Enzyme Inhibitors

Testosterone 5-alpha-Reductase

 

PMID: 12570838 [PubMed - indexed for MEDLINE]

 

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Planta Med. 2000 Feb;66(1):16-9. Related Articles, Links

 

 

The 5 alpha-reductase inhibitory components from heartwood of Artocarpus incisus: structure-activity investigations.

 

Shimizu K, Fukuda M, Kondo R, Sakai K.

 

Department of Forest Products, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.

 

The methanol extract of heartwood of Artocarpus incisus showed potent 5 alpha-reductase inhibitory activity. We investigated the 5 alpha-reductase inhibitory effects of nine compounds isolated from A. incisus. Chlorophorin (IC50 = 37 microM) and artocarpin (IC50 = 85 microM) showed more potent inhibitory effects than did alpha-linolenic acid, which is known as a naturally occurring potent inhibitor. Structure-activity investigations suggested that the presence of an isoprene substituent (prenyl and geranyl) would enhance 5 alpha-reductase inhibitory effects.

 

MeSH Terms:

Animals

Enzyme Inhibitors/chemistry

Enzyme Inhibitors/pharmacology*

Female

Rats

Rats, Sprague-Dawley

Structure-Activity Relationship

Support, Non-U.S. Gov't

Testosterone 5-alpha-Reductase/antagonists & inhibitors*

Trees/chemistry*

 

Substances:

Enzyme Inhibitors

Testosterone 5-alpha-Reductase

 

PMID: 10705727 [PubMed - indexed for MEDLINE]

 

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un'altro.....

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...finalmente la boehmeria niponivea...

 

Biosci Biotechnol Biochem. 2000 Apr;64(4):875-7. Related Articles, PC Compound via MeSH, PC Substance via MeSH, Books, LinkOut

 

 

Steroid 5alpha-reductase inhibitory activity and hair regrowth effects of an extract from Boehmeria nipononivea.

Shimizu K, Kondo R, Sakai K, Shoyama Y, Sato H, Ueno T.

 

Department of Forest Products, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.

 

The acetone extract of Boehmeria nipononivea showed both potent 5alpha-reductase inhibitory activity and hair regrowth promotion effects on mice. 5alpha-Reductase inhibitory activity-guided fractionation led to six active fatty acids: alpha-linolenic, linoleic, palmitic, elaidic, oleic and stearic acids. The extract of B. nipononivea, and alphalinolenic, elaidic and stearic acids exhibited a hair regrowth effect.

 

MeSH Terms:

Acetone

Alopecia/drug therapy*

Animals

Enzyme Inhibitors/pharmacology

Fatty Acids/therapeutic use*

Hair/growth & development*

Male

Mice

Mice, Inbred C57BL

Plant Extracts/pharmacology*

Rosales/chemistry*

Support, Non-U.S. Gov't

Testosterone 5-alpha-Reductase/antagonists & inhibitors*

 

Substances:

Enzyme Inhibitors

Fatty Acids

Plant Extracts

Acetone

Testosterone 5-alpha-Reductase

 

PMID: 10830511 [PubMed - indexed for MEDLINE]

 

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