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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Beranic, Natasa Stefane, Bogdan Brus, Boris Gobec, Stanislav Rizner, Tea Lanisnik |
| Description | Country affiliation: Slovenia Author Affiliation: Beranic N ( Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.) |
| Abstract | The imbalance in expression of the human aldo-keto reductases AKR1C1-AKR1C3 is related to different hormone dependent and independent cancers and some other diseases. The AKR1C1-3 enzymes thus represent emerging targets for the development of new drugs. Currently, various enzymatic assays are used in the search for AKR1C inhibitors, and consequently the results of different research groups are not necessarily comparable. During our recent search for AKR1C inhibitors, we found a cyclopentanol derivative (2-(4-chlorobenzylidene)cyclopentanol, CBCP-ol) and its respective cyclopentanone counterpart (2-(4-chlorobenzylidene)cyclopentanone, CBCP-one) that acted as AKR1C substrates. We determined the kinetic parameters KM, kcat and kcat/KM for oxidation of CBCP-ol and reduction of CBCP-one by AKR1C enzymes in the presence of NAD(+)/NADP(+) and NADH/NADPH, respectively. The catalytic efficiencies for the oxidation of CBCP-ol in the presence of NAD(+) or NADP(+) were in general higher when compared to the catalytic efficiencies for reduction of CBCP-one in the presence of NADH or NADPH. When NADPH was used, as compared to NADH, the reductions of CBCP-one by AKR1C1, AKR1C2 and AKR1C3 were 14-, 51- and 31-fold more efficient, respectively. When comparing to oxidations of the well-known artificial substrates, 1-acenaphthenol and S-tetralol, we observed similar catalytic efficiencies as for CBCP-ol oxidation with NAD(+) and NADP(+). The comparison of CBCP-one reduction with NADPH to reductions of physiological substrates revealed in general higher efficiencies, except for reduction of 9-cis-retinaldehyde by AKR1C3. This NADPH-dependent reduction of CBCP-one was then used to re-evaluate inhibitory potencies of the known inhibitors of the target AKR1C3 and the anti-target AKR1C2, medroxyprogesterone acetate and ursodeoxycholic acid, respectively, showing Ki constants similar to the reported values. Our data thus confirm that the new enzymatic assays with two cyclopentane substrates CBP-ol and CBP-one, and especially reduction of CBCP-one with NADPH, are appropriate for the evaluation of AKR1C inhibitors. |
| File Format | HTM / HTML |
| ISSN | 00092797 |
| Issue Number | 1-3 |
| Volume Number | 202 |
| e-ISSN | 18727786 |
| Journal | Chemico-Biological Interactions |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2013-02-25 |
| Publisher Place | Ireland |
| Access Restriction | One Nation One Subscription (ONOS) |
| Subject Keyword | Discipline Biochemistry Discipline Pharmacology 20-hydroxysteroid Dehydrogenases Antagonists & Inhibitors Metabolism 3-hydroxysteroid Dehydrogenases Enzyme Assays Methods Hydroxyprostaglandin Dehydrogenases Alcohol Oxidoreductases Aldehyde Reductase Catalysis Cyclopentanes Pharmacology Enzyme Inhibitors Humans Kinetics Medroxyprogesterone Acetate Nad Nadp Oxidation-reduction Ursodeoxycholic Acid Journal Article Research Support, Non-u.s. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Medicine Toxicology |
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