MK386: a potent, selective inhibitor of the human type 1 5alpha-reductase.
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.
Department of Enzymology, Merck Research Laboratories, Rahway, NJ 07065, USA.
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Ellsworth
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Azzolina
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Baginsky
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Bull
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Chang
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Cimis
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Mitra
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Toney
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Bakshi
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Rasmusson
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Tolman
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Harris
D058891:5-alpha Reductase Inhibitors; D000085:Acetates / Q000378:metabolism; D001141:Aromatase / Q000378:metabolism; D001378:Azasteroids / Q000378:metabolism / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular; D002462:Cell Membrane; D002784:Cholesterol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism; D007700:Kinetics; D011284:Pregnenolone / Q000378:metabolism; D011485:Protein Binding; D011944:Receptors, Androgen / Q000378:metabolism; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured
C090665:4,7beta-dimethyl-4-azacholestan-3-one; D058891:5-alpha Reductase Inhibitors; D000085:Acetates; D001378:Azasteroids; D004791:Enzyme Inhibitors; D011944:Receptors, Androgen; D011994:Recombinant Proteins; D011284:Pregnenolone; D002784:Cholesterol; D006913:Hydroxysteroid Dehydrogenases; D001141:Aromatase