Overexpression of Aldo-Keto Reductase 1C3 in LNCaP Cells Diverts Androgen Metabolism Towards Testosterone Resulting in Resistance to the 5α-Reductase Inhibitor Finasteride

May 2012 in “ The Journal of Steroid Biochemistry and Molecular Biology ”

Michael C. Byrns, Rebekka Mindnich, Ling Duan, Trevor M. Penning

AKR1C3 androgen metabolism testosterone 5α-reductase inhibitor finasteride A4-Adione 5a-androstane-3,17-dione 5a-DHT androgen receptor prostate cancer 5-alpha-reductase inhibitor Propecia androstenedione DHT

TLDR Too much AKR1C3 enzyme causes resistance to finasteride by increasing testosterone.

The study found that overexpression of the enzyme AKR1C3 in LNCaP cells led to a diversion of androgen metabolism towards testosterone, resulting in resistance to the 5α-reductase inhibitor finasteride. This was due to AKR1C3 redirecting A4-Adione metabolism towards testosterone production, leading to increased levels of testosterone and decreased sensitivity to finasteride. The study suggests that inhibition of AKR1C3 could prevent the conversion of A4-Adione to testosterone and the conversion of 5a-androstane-3,17-dione to 5a-DHT, which are potent ligands for the AR, and could have therapeutic consequences for the use of inhibitors that target 5α-reductase in prostate cancer.

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Mechanism-Based Inhibition of Human Steroid 5α-Reductase by Finasteride: Enzyme-Catalyzed Formation of NADP-Dihydrofinasteride, a Potent Bisubstrate Analog Inhibitor

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