Drug-metabolizing enzymes and transporters: expression in the human prostate and roles in prostate drug disposition.

摘要

Local biotransformation enzymes and transporter proteins in tissues may exert a profound effect on drug pharmacokineticsin 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 cytochrome P450 (CYP) phase I and phase II conjugation enzymes and drug transporters. Phase I drug-metabolizing enzymes detected in the human prostate include CYP, CYP1A1, CYP1A2, CYP1B1, CYP2C19, CYP2D6, CYP3A5, and CYP4B1 in both normal and tumoroustissue; CYP1A1, CYP1A2, and CYP1B1 in BPH tissues; and CYP1A1 and CYP1A2 in prostate cancer cell lines and normal prostate epithelial cells. Epoxide hydrolasewas also found in prostate tumor and nonneoplastic tissue. Phase II metabolizing enzymes detected in the prostate were glutathione S-transferases (GSTs) GST-alpha, GST-mu, and GST-pi, and N-acetyltransferase (NAT) iso-forms, NAT1 and NAT2. Prostate tissue contains the multidrugresistance protein (MRP) transporters MRP1, MRP2, MRP3, and MRP4, and the multidrug resistance (MDR)-1 protein (P-glycoprotein; P-gp). Metabolism of drugs used in BPH (eg, finasteride and tamsulosin) and anticancer 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-metabolizing 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 facilitateentry 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.Use of pharmacologic agents in the treatment of benign prostatic hyperplasia (BPH) and prostate cancer is well established. Refinements to therapy with existing agents and the development of safer and more effective agents are complementary approaches for the optimization of therapy. The therapeutic goals in BPH treatment are the reduction of prostate volume, minimizing risk of acute urinary retention and the prevention of BPH-related surgery and deterioration of the quality of life of the patient. In prostate cancer, drug therapy aims to inhibit the growth of androgen-dependent tumors, to prevent their progression to the hormone-independent metastatic stage, and to decrease morbidity and mortality in advanced disease.Factors that influence intracellular drug concentrations and the duration of drug action are important determinants of success in the treatment of BPH and prostate cancer. Rates of drug absorption and elimination are controlled by biotransformation enzymes and transporter proteins. The principal site of drug biotransformation is the liver, but it is now clear that drug-metabolizing enzymes are present in extrahepatic tissues, including the prostate, and may affect local rates of drug biotransformation. Similarly, drug transporters are widely distributed in tissues and overexpression of these genes is associated with drug resistance, especially in tumor cells, because of the inability to maintain therapeutic drug levels.