Pharmacogenetic analysis of human steroid 5α reductase type II: comparison of finasteride and dutasteride

Abstract

Human steroid 5 -reductase type II is a prostate-specific, membrane-associated enzyme that catalyzes the conversion of testosterone to dihydrotestosterone, the most potent androgen in the prostate gland. Genetic variants of this enzyme have been associated with both the development and the progression of prostate cancer. Both finasteride and dutasteride are competitive inhibitors of the type II steroid 5 -reductase that have been effectively used for the treatment of benign prostatic hyperplasia. Finasteride has also been successfully utilized for prostate cancer chemoprevention. We here investigate 5 -reductase inhibition assays in vitro to measure the effect of incubation time on the apparent inhibition constant (K i ) for both constitutional and somatic (prostate cancer) enzyme variants. Our systematic pharmacogenetic analysis shows that both finasteride and dutasteride are slow, time-dependent inhibitors of steroid 5 -reductase type II, and that the inhibition kinetics depend on the 5 -reductase genotype. We also show that, overall, dutasteride is a more efficient steroid 5 -reductase inhibitor than finasteride. Based on our data, we are able to map areas of the enzyme that are responsible for this time-dependent inhibition for either (or both) enzyme inhibitor(s). This comprehensive pharmacogenetic analysis of steroid 5 -reductase variants unveiled significant pharmacogenetic variation for both finasteride and dutasteride and thus should be taken into account when designing protocols for treatment and/or chemoprevention of prostatic diseases with either one of these 5 -reductase inhibitors since there is considerable pharmacogenetic variation for both drugs.

Dutasteride affects progesterone metabolizing enzyme activity/expression in human breast cell lines resulting in suppression of cell proliferation and detachment

“…Dutasteride has been shown to act as a competitive inhibitor of testosterone 5␣-reductase activity [26] and our enzyme studies on cell-free preparations indicate that it may also inhibit progesterone 5␣-reductase activity in a similar manner. However there may be an additional component to the progesterone 5␣-reductase inhibition by dutasteride.…”

“…The 4-azasteroid, dutasteride, is a potent inhibitor of both 5␣-reductase isoenzymes [6] and has been used in several trials to test the efficacy and safety in men with benign prostatic hyperplasia [7,10,25], in a prostate cancer prevention trial (REDUCE) [14] and in men with known prostate cancer [13]. While numerous studies have established that dutasteride effectively inhibits conversion of testosterone to DHT in vitro [26] and in vivo [9,27,28], the results reported here are the first to show that dutasteride is also a potent inhibitor of progesterone 5␣-reduction.…”

Genetic variations in genes involved in testosterone metabolism are associated with prostate cancer progression: A Spanish multicenter study

“…The consequences this specific haplotype may have in the function of the enzyme have to be explored. Recently, a systematic analysis of both constitutional and somatic (PCa) variants of steroid 5α-reductase type II indicated significant pharmacogenetic variation for both finasteride and dutasteride response and allowed to map areas of the wild-type enzyme that are responsible for the timedependent inhibition for either (or both) enzyme inhibitor(s) [26]. SNPs are the basics of pharmacogenetics, and it is possible that individual SNPs or specific haplotypes can explain this heterogeneity.…”

Prostate cancer: germline prediction for a commonly variable malignancy

“…Variants in ABCB1 do not predict response to taxanes [ 70 ] . Interestingly, in view of the data supporting a preventive role for fi nasteride and dutasteride [ 71,72 ] , germline variants in 5 α -reductase type II may alter the activity of the drugs although replication of a single report is required [ 73 ] . Trinucleotide repeat length in the androgen receptor has been investigated as a predictor of response to androgen-deprivation therapy, but both longer [ 74 ] and shorter [ 75 ] repeats have been associated with better response, diminishing the interest in pursuing this approach.…”