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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