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Published-Ahead-of-Print December 5, 2005, DOI:10.2164/jandrol.05113

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Drug Metabolising Enzymes and Transporters: Expression in the Human Prostate and Roles in Prostate Drug Disposition

Regina Obligacion , Michael Murray , and Iqbal Ramzan *

* To whom correspondence should be addressed. E-mail: iqbalr{at}pharm.usyd.edu.au.

Local biotransformation enzymes and transporter proteins in tissues may exert a profound effect on drug pharmacokinetics in those tissues. Thus the use of drugs for the treatment of benign prostatic hyperplasia (BPH) and cancer of the prostrate may be influenced by high level expression of CYP phase I and phase II conjugation enzymes and drug transporters. Phase I drug metabolizing enzymes detected in the human prostate include cytochrome P450, CYP1A1, CYP1A2, CYP1B1, CYP2C19, CYP2D6, CYP3A5, CYP4B1 in both normal and tumorous tissue; CYP1A1, CYP1A2, CYP1B1 in BPH tissues and CYP1A1 and CYP1A2 in prostate cancer cell lines and normal prostate epithelial cells. Epoxide hydrolase was also found in prostate tumor and non-neoplastic tissue. Phase II metabolizing enzymes detected in the prostate were glutathione S-transferases GST-{alpha}, GST-µ and GST-{pi} and N-acetyltransferase isoforms NAT1 and NAT2. Prostate tissue contains the drug transporters MRP1, MRP2, MRP3, MRP4 and MDR1 (Pgp). Metabolism of drugs used in BPH (e.g., finasteride and tamsulosin) and anti-cancer agents have been examined in the liver or liver preparations but not in the prostate or prostate tissue/cell lines. Thus the published data to date shows that the prostate contains the major phase I and II drug metabolising enzymes as well as drug transporters. Future studies should examine the ability of the prostate to metabolize drugs used in either BPH or prostate cancer and to gauge the ability of the identified drug transporters to facilitate entry into or efflux from the prostate. Such studies could identify the principal determinants of the local (prostate) concentrations of these therapeutic agents when used in either BPH or prostate cancer.






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Copyright © 2005 by The American Society of Andrology.