MK386: a potent, selective inhibitor of the human type 1 5α-reductase
| Autor: | Kenneth P. Ellsworth, S. Mitra, Georgianna Harris, G.R. Rasmusson, Raman K. Bakshi, Jeffrey H. Toney, B. Chang, Walter F. Baginsky, R. L. Tolman, B. Azzolina, George Cimis, Herbert G. Bull |
|---|---|
| Rok vydání: | 1996 |
| Předmět: |
Carcinoma
Hepatocellular Endocrinology Diabetes and Metabolism medicine.medical_treatment Clinical Biochemistry Acetates Reductase Biochemistry Isozyme Steroid 5-alpha Reductase Inhibitors Aromatase Endocrinology Tumor Cells Cultured medicine Humans Potency Enzyme Inhibitors Molecular Biology Testosterone chemistry.chemical_classification biology Cell Membrane Hydroxysteroid Dehydrogenases Cell Biology Recombinant Proteins Kinetics Cholesterol Enzyme chemistry Receptors Androgen Enzyme inhibitor Azasteroids Pregnenolone Dihydrotestosterone biology.protein Molecular Medicine Protein Binding medicine.drug |
| Zdroj: | The Journal of Steroid Biochemistry and Molecular Biology. 58:377-384 |
| ISSN: | 0960-0760 |
| DOI: | 10.1016/0960-0760(96)00050-7 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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