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URL: https://pubmed.ncbi.nlm.nih.gov/21142863/

⇱ Finasteride metabolism and pharmacogenetics: new approaches to personalized prevention of prostate cancer - PubMed


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Abstract

Incidences of prostate cancer in most countries are increasing owing to better detection methods; however, prevention with the use of finasteride, a very effective steroid 5α-reductase type II inhibitor, has been met with mixed success. A wide interindividual variation in response exists and is thought to be due to heritable factors. This article summarizes the literature that attempts to elucidate the molecular mechanisms of finasteride in terms of its metabolism, excretion and interaction with endogenous steroid molecules. We describe previously reported genetic variations of steroid-metabolizing genes and their potential association with finasteride efficacy. Based on the literature, we outline directions of research that may contribute to understanding the interindividual variation in finasteride prevention and to the future development of personalized medicine.

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Conflict of interest statement

competing interests disclosure

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Figures

👁 Figure 1.
Figure 1.. Prostate tissue growth and differentiation.
Circulating testosterone diffuses into prostatic cells, where it is irreversibly converted into the more potent androgen DHT via the NADPH-dependent reduction catalyzed by the steroid 5α-reductase type II and, to a lesser extent, by steroid 5α-reductase type I. DHT binds to the androgen receptors located on the nuclear membrane. Two DHT–receptor complexes are formed in the nucleus that bind to specific regions of the DNA – the androgen response elements – with high affinity, enhancing the production of regulatory proteins involved in cell proliferation and prostate-specific antigen. Finasteride, a steroid 5α-reductase type II inhibitor, causes an intra-prostatic DHT decrease, ultimately leading to apoptosis. DHT: 5α-dihydrotestosterone; NADP: Nicotinamide adenine dinucleotide; NADPH: Nicotinamide adenine dinucleotide phosphate. Data taken from [125].
👁 Figure 2.
Figure 2.. Metabolism of finasteride.
During phase I, finasteride is metabolized to ω-hydroxyfinasteride and finasteride-ω-oic acid, a process mediated by CYP3A4. Phase II metabolism involves glucuronidation of ω-hydroxyfinasteride and finasteride-ω-oic acid metabolites by UGT1A4 and UGT1A3, respectively. Data taken from [65].

References

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