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| Title: MK386: a potent, selective inhibitor of the human type 1
5alpha-reductase. |
| Title Abreviation: J Steroid Biochem Mol Biol |
Date of Pub: 1996 Jul |
| Author: Ellsworth K; Azzolina B; Baginsky W; Bull H; Chang B; Cimis
G; Mitra S; Toney J; Bakshi RK; Rasmusson GR; Tolman RL; Harris GS; |
| Issue/Part/Supplement: 4 |
Volume Issue: 58 |
Pagination: 377-84 |
| MESH Headings: Acetates (ME); Aromatase (ME); Azasteroids (ME/*PD);
Carcinoma, Hepatocellular; Cell Membrane; Cholesterol (ME); Enzyme Inhibitors (PD); Human;
Hydroxysteroid Dehydrogenases (ME); Kinetics; Pregnenolone (ME); Protein Binding;
Receptors, Androgen (ME); Recombinant Proteins; Testosterone 5-alpha-Reductase (*AI);
Tumor Cells, Cultured; -RN-; |
| Journal Title Code: AX4 |
Publication Type: JOURNAL ARTICLE |
| Date of Entry: 961218N |
Entry Month: 9702 |
| Country: ENGLAND |
Index Priority: 2 |
| Language: Eng |
Unique Identifier: 97060386 |
| Unique Identifier: 97060386 |
ISSN: 0960-0760 |
| Abstract: Steroid 5alpha-reductase is required for the conversion
of testosterone to dihydrotestosterone. Localization of type 1 5alpha-reductase in the
sebaceous gland of skin offers the possibility for selective inhibition of this isozyme as
a treatment for acne. The goals of these studies are to demonstrate the mechanism of
inhibition of MK386 and its selectivity for type 1 5alpha-reductase. The apparent potency
of MK386 differed depending on the source of the enzyme (i.e. recombinant vs. native), yet
selectivity for type 1 5alpha-reductase was unchanged. Our results indicate that the
apparent potency of MK386 is modulated by the membrane concentration of the assay. These
results suggest that MK386 has a high affinity for the lipid-rich membrane environment of
5alpha-reductase. MK386 was also found to be a slow binding inhibitor of type 1
5alpha-reductase. However, the cause of this time-dependent inhibition is unrelated to
partitioning of the inhibitor into the membrane because similar studies with type 2
5alpha-reductase indicate that MK386 is a reversible, competitive inhibitor. A number of
counterscreens were developed to demonstrate that MK386 is a poor inhibitor of other
steroid metabolizing enzymes. |
| Abstract By: Author |
| Address: Department of Enzymology, Merck Research Laboratories,
Rahway, NJ 07065, USA. |
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