Sandbox 45673
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Finasteride is a 5α-reductase inhibitor. There are three isoforms of 5α-reductase, types I, II, and III. While the drug has a higher affinity for the type II enzyme, it also inhibits the function of the type I and no affinity for type III.<ref name="four"> Schieck, Cynthia L.(1998, August) "Finasteride (Propecia ®)". http://www.chm.bris.ac.uk/motm/finasteride/Finasteride%20(Propecia)%20-%20Feature%20Molecule.htm </ref>The enzyme 5α-reductase turns Finasteride into dihydrofinasteride through an enzyme bound, NADP-dihydrofinasteride adduct.. However, Finasteride , having a high affinity for 5α-reductase, covalently binds to the enzyme as a Michael acceptor, through a functionally irreversible reaction which essentially halts the chemical process before the NADP-Dihydrofinasteride complex can be reduced to Dihydrofinasteride because of a change in the carbanion position in respect to its placement on the similar enolate intermediate created in the reaction where testosterone is converted into DHT by 5α-reductase.(figure 3) However, the NADP-dihydrofinasteride complex does eventually break down with a half life of about 1 month at 37˚C., which is why patients must continue taking the drug.<ref name="five"> Bull, Herbert G.*Garcia-Calvo,Margarita Andersson,Stefan†, Baginsky, Walter F.,Chan,H. Karen,Ellsworth,‡ Dina E., Miller,§ Randall R., Stearns,Ralph A.,Bakshi,Raman K.,Rasmusson, Gary H.,Tolman,Richard L., Myers,Robert W.,Kozarich,John W.,Harris,Georgianna S. (1995, August 6) Mechanism-Based Inhibition of Human Steroid 5R-Reductase by Finasteride: Enzyme-Catalyzed Formation of NADP-Dihydrofinasteride, a Potent Bisubstrate Analog Inhibitor. http://pubs.acs.org/doi/pdf/10.1021/ja953069t</ref> | Finasteride is a 5α-reductase inhibitor. There are three isoforms of 5α-reductase, types I, II, and III. While the drug has a higher affinity for the type II enzyme, it also inhibits the function of the type I and no affinity for type III.<ref name="four"> Schieck, Cynthia L.(1998, August) "Finasteride (Propecia ®)". http://www.chm.bris.ac.uk/motm/finasteride/Finasteride%20(Propecia)%20-%20Feature%20Molecule.htm </ref>The enzyme 5α-reductase turns Finasteride into dihydrofinasteride through an enzyme bound, NADP-dihydrofinasteride adduct.. However, Finasteride , having a high affinity for 5α-reductase, covalently binds to the enzyme as a Michael acceptor, through a functionally irreversible reaction which essentially halts the chemical process before the NADP-Dihydrofinasteride complex can be reduced to Dihydrofinasteride because of a change in the carbanion position in respect to its placement on the similar enolate intermediate created in the reaction where testosterone is converted into DHT by 5α-reductase.(figure 3) However, the NADP-dihydrofinasteride complex does eventually break down with a half life of about 1 month at 37˚C., which is why patients must continue taking the drug.<ref name="five"> Bull, Herbert G.*Garcia-Calvo,Margarita Andersson,Stefan†, Baginsky, Walter F.,Chan,H. Karen,Ellsworth,‡ Dina E., Miller,§ Randall R., Stearns,Ralph A.,Bakshi,Raman K.,Rasmusson, Gary H.,Tolman,Richard L., Myers,Robert W.,Kozarich,John W.,Harris,Georgianna S. (1995, August 6) Mechanism-Based Inhibition of Human Steroid 5R-Reductase by Finasteride: Enzyme-Catalyzed Formation of NADP-Dihydrofinasteride, a Potent Bisubstrate Analog Inhibitor. http://pubs.acs.org/doi/pdf/10.1021/ja953069t</ref> | ||
- | [[Image: Biochem group project.PNG|thumb|500px|right|'''Fig. 3'''. Proposed mechanism of inhibition by Bull et. al. Image shows how the inhibition of 5alpha-reductase is achieved as Finasteride is used as a substrate to create an enolate intermediate, similar to the one made during the reduction of testosterone. However, the complex created does not allow for the proton transfer needed to complete the reduction of NADP-Dihydrofinasteride to Finasteride, because of the change in the carbanion position. PADPR= phosphoadenosine diphosphoribose<ref name="five">Bull, Herbert G.*Garcia-Calvo,Margarita Andersson,Stefan†, Baginsky, Walter F.,Chan,H. Karen,Ellsworth,‡ Dina E., Miller,§ Randall R., Stearns,Ralph A.,Bakshi,Raman K.,Rasmusson, Gary H.,Tolman,Richard L., Myers,Robert W.,Kozarich,John W.,Harris,Georgianna S. (1995, August 6) Mechanism-Based Inhibition of Human Steroid 5R-Reductase by Finasteride: Enzyme-Catalyzed Formation of NADP-Dihydrofinasteride, a Potent Bisubstrate Analog Inhibitor. | + | [[Image: Biochem group project.PNG|thumb|500px|right|'''Fig. 3'''. Proposed mechanism of inhibition by Bull et. al. Image shows how the inhibition of 5alpha-reductase is achieved as Finasteride is used as a substrate to create an enolate intermediate, similar to the one made during the reduction of testosterone. However, the complex created does not allow for the proton transfer needed to complete the reduction of NADP-Dihydrofinasteride to Finasteride, because of the change in the carbanion position. PADPR= phosphoadenosine diphosphoribose<ref name="five">Bull, Herbert G.*Garcia-Calvo,Margarita Andersson,Stefan†, Baginsky, Walter F.,Chan,H. Karen,Ellsworth,‡ Dina E., Miller,§ Randall R., Stearns,Ralph A.,Bakshi,Raman K.,Rasmusson, Gary H.,Tolman,Richard L., Myers,Robert W.,Kozarich,John W.,Harris,Georgianna S. (1995, August 6) Mechanism-Based Inhibition of Human Steroid 5R-Reductase by Finasteride: Enzyme-Catalyzed Formation of NADP-Dihydrofinasteride, a Potent Bisubstrate Analog Inhibitor. </ref>]] |
+ | ; | ||
==Medical Uses== | ==Medical Uses== | ||
'''Benign Prostatic Hyperplasia (BPH)''' | '''Benign Prostatic Hyperplasia (BPH)''' | ||
- | [[Aromatase]] and 5α-reductase is responsible for converting androgen hormones into estrogen and dihydrotestosterone (DHT). This chemical process of androgen hormones leads to a decrease in testosterone, but raises levels of DHT and estrogen. Estrogen is a key role in cells proliferating in the prostate and DHT is an anabolic hormone much more potent (dissociated from the androgen receptor slowly) than testosterone that when combined, causes a synergy to induce BPH. The enzyme 5α-reductase is responsible for the synthesis of DHT in the prostate from circulating testosterone. 5α-reductase is located in the stromal cells, which is the main site for the synthesis of DHT, but it can also diffuse into epithelial cells close-by. In both stromal and epithelial cells, DHT binds to nuclear androgen receptors and signals for transcription for cell growth. Finasteride is used to inhibit the 5α-reductase enzyme, which blocks the conversion of testosterone and inhibits the production of DHT, reducing prostate volume and BPH symptoms (urinating complication). Using finasteride could increase the risk for erectile dysfunction, decrease libido, and ejaulation disorder due to 5α-reductase being inhibited. | + | [[Aromatase]] and 5α-reductase is responsible for converting androgen hormones into estrogen and dihydrotestosterone (DHT). This chemical process of androgen hormones leads to a decrease in testosterone, but raises levels of DHT and estrogen<ref name="six">Tacklind, J., Fink, H.A., MacDonald, R., Rutks, I., Wilt, T.J. (2010). Finasteride for benign prostatic hyperplasia. Cochrane database of systematic reviews 2010, Issue 10. Art. No.: CD006015. DOI: 10.1002/14651858.CD006015.pub3. </ref>]]. Estrogen is a key role in cells proliferating in the prostate and DHT is an anabolic hormone much more potent (dissociated from the androgen receptor slowly) than testosterone that when combined, causes a synergy to induce BPH. The enzyme 5α-reductase is responsible for the synthesis of DHT in the prostate from circulating testosterone. 5α-reductase is located in the stromal cells, which is the main site for the synthesis of DHT, but it can also diffuse into epithelial cells close-by. In both stromal and epithelial cells, DHT binds to nuclear androgen receptors and signals for transcription for cell growth. Finasteride is used to inhibit the 5α-reductase enzyme, which blocks the conversion of testosterone and inhibits the production of DHT, reducing prostate volume and BPH symptoms (urinating complication). Using finasteride could increase the risk for erectile dysfunction, decrease libido, and ejaulation disorder due to 5α-reductase being inhibited. |
'''Prostate Cancer''' | '''Prostate Cancer''' |
Revision as of 12:34, 6 December 2016
N-(1,1-dimethylethyl)-3-oxo-(5α,17β)-4-azaandrost-1-ene-17-carboxamide (Finasteride)
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References
- ↑ 1.0 1.1 I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 121, 246. ISBN 978-94-011-4439-1
- ↑ 2.0 2.1 Yamana K, Labrie F, Luu-The V (January 2010). Human type 3 5α-reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited by finasteride and dutasteride. Hormone Molecular Biology and Clinical Investigation. 2 (3). doi:10.1515/hmbci.2010.035
- ↑ Varothai, S; Bergfeld, WF (Jul 2014). "Androgenetic alopecia: an evidence-based treatment update.". American journal of clinical dermatology. 15 (3): 217–30. doi:10.1007/s40257-014-0077-5. PMID 24848508
- ↑ 4.0 4.1 Lednicer D (2011). Steroid Chemistry at a Glance. Hoboken: Wiley. ISBN 978-0-470-66084-3
- ↑ Burkhard Fugmann; Susanne Lang-Fugmann; Wolfgang Steglich (28 May 2014). RÖMPP Encyclopedia Natural Products, 1st Edition, 2000. Thieme. pp. 1918–. ISBN 978-3-13-179551-9
- ↑ Schieck, Cynthia L.(1998, August) "Finasteride (Propecia ®)". http://www.chm.bris.ac.uk/motm/finasteride/Finasteride%20(Propecia)%20-%20Feature%20Molecule.htm
- ↑ 7.0 7.1 Bull, Herbert G.*Garcia-Calvo,Margarita Andersson,Stefan†, Baginsky, Walter F.,Chan,H. Karen,Ellsworth,‡ Dina E., Miller,§ Randall R., Stearns,Ralph A.,Bakshi,Raman K.,Rasmusson, Gary H.,Tolman,Richard L., Myers,Robert W.,Kozarich,John W.,Harris,Georgianna S. (1995, August 6) Mechanism-Based Inhibition of Human Steroid 5R-Reductase by Finasteride: Enzyme-Catalyzed Formation of NADP-Dihydrofinasteride, a Potent Bisubstrate Analog Inhibitor. http://pubs.acs.org/doi/pdf/10.1021/ja953069t
- ↑ Tacklind, J., Fink, H.A., MacDonald, R., Rutks, I., Wilt, T.J. (2010). Finasteride for benign prostatic hyperplasia. Cochrane database of systematic reviews 2010, Issue 10. Art. No.: CD006015. DOI: 10.1002/14651858.CD006015.pub3.
- ↑ Olsen, E. A., Hordinsky, M., & Whiting, D., et al. (2006, December).
- ↑ Leyden, James et al.(June 1999)."Finasteride in the treatment of men with frontal male pattern hair loss." Journal of the American Academy of Dermatology. Volume 40 , Issue 6 , 930 - 937