17.beta.-(N-tert-Butylcarbamoyl)-4-aza-5.alpha.-androstan-1-en-3-one Is an Active Site-Directed Slow Time-Dependent Inhibitor of Human Steroid 5.alpha.-Reductase 1

Tian, Gaochao; Jd, Stuart; Ml, Moss; Pl, Domanico; Hn, Bramson; Ir, Patel; Sh, Kadwell; Lk, Overton; Ta, Kost; Ra, Mook

doi:10.1021/bi00174a041

Cited by 54 publications

(39 citation statements)

References 23 publications

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“…The apparent K i for both finasteride and dutasteride in those experiments was calculated after transient expression of the reconstructed variant clones in mammalian cells followed by 10-min in vitro enzyme assays (Makridakis et al 2000(Makridakis et al , 2004. However, finasteride is a slow, time-dependent inhibitor of steroid 5 -reductase (Faller et al 1993, Tian et al 1994, 1995. Therefore, longer finasteride incubations with the wild-type enzyme are expected to result in better inhibition, or lower apparent K i (see e.g.…”

Section: Resultsmentioning

confidence: 99%

“…Those results, however, were based on 10-min reactions, while finasteride is a slow, time-dependent inhibitor of steroid 5 -reductase (e.g. Faller et al 1993, Tian et al 1994. Thus, we reasoned that longer incubations with either inhibitor would be better approximations of the true inhibition in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Finasteride, however, dissociates from the enzyme very slowly, and therefore is a time-dependent inhibitor of steroid 5 -reductase (Faller et al 1993, Tian et al 1994, 1995. In addition, dutasteride (Frye et al 1998), like finasteride, retains the 1,2 bond that is critical for time-dependent inhibition in 4-azasteroids (Russell & Wilson 1994).…”

Section: Introductionmentioning

confidence: 99%

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

Makridakis

Reichardt

2005

Journal of Molecular Endocrinology

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Makridakis

Reichardt

2005

Journal of Molecular Endocrinology

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“…Although of interest in relation to alcoholism risk, the GABRA2 polymorphism that was examined in this study as a moderator of alcohol's effects has not been shown to be functional; the variation in this gene that underlies the association with alcohol dependence remains to be determined. Although finasteride is a potent antagonist of type 2 5AR, it has modest antagonist activity at type 1 5AR (Tian et al, 1994;Tian, 1996), the predominant isoform in the mature human brain (Poletti et al, 1998;Stoffel-Wagner et al, 1998). To compensate for the lower antagonist activity of finasteride at the human brain type 1 5AR, we administered a high dose of the drug (ie a total of 200 mg over 24 h, which is 40 times the standard daily dose).…”

Section: Subjective Effects Of Alcoholmentioning

confidence: 99%

GABRA2 Alleles Moderate the Subjective Effects of Alcohol, Which are Attenuated by Finasteride

Pierucci‐Lagha

Covault

Feinn

et al. 2005

Neuropsychopharmacol

133

109

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GABA A receptors are involved in the subjective effects of alcohol. Endogenous neuroactive steroids interact with GABA A receptors to mediate several behavioral effects of alcohol in rodents. Based on a haplotypic association of alcohol dependence with the gene encoding the GABA A receptor a-2 subunit (GABRA2), we examined whether GABRA2 alleles are associated with the subjective response to alcohol. We also examined whether finasteride (a 5-a steroid reductase inhibitor), which blocks the synthesis of some neuroactive steroids, reduces the subjective response to alcohol. In all, 27 healthy social drinkers (15 males) completed a randomized, double-blind, placebo-controlled study of high-dose finasteride. After being pretreated with study drug, subjects consumed three alcoholic drinks. Subjective effects were measured repeatedly over the ascending blood alcohol curve. To examine the moderating role of genetic variation in GABRA2, a single-nucleotide polymorphism that was informative in association studies was included as a factor in the analysis. Subjects homozygous for the more common A-allele (n ¼ 7) showed more subjective effects of alcohol than did individuals with one or two copies of the alcohol dependence-associated G-allele (n ¼ 20, including two homozygotes). Among the A-allele homozygotes, there was a greater reduction in several subjective effects during the finasteride session compared to the placebo session. These findings provide preliminary evidence that the risk of alcoholism associated with GABRA2 alleles may be related to differences in the subjective response to alcohol. The effects of finasteride provide indirect evidence for a mediating role of neuroactive steroids in some of the subjective effects of alcohol.

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“…Finastride, a synthetic antiandrogenic drug is marketed for Benign prostrate hyperplasia and androgenic alopecia and the mechanism involved is inhibition of 5α-reductase activity (Tian et al, 1994) Finasteride also has been used topically to treat androgenetic alopecia (Mazzarella et al, 1997). For the treatment of androgen related disorders like androgenetic alopecia, fi nasteride has been approved by USFDA (Libecco & Bergfeld, 2004), but there are many side effects associated with fi nasteride.…”

Section: Introductionmentioning

confidence: 99%

Effect of petroleum ether and ethanol fractions of seeds of Abrus precatorius on androgenic alopecia

Upadhyay¹,

Dixit²,

Ghosh³

et al. 2012

Rev. bras. farmacogn.

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Seeds of Abrus precatorius L., Fabaceae, are commonly used as purgative, emetic, aphrodisiac and in nervous disorder in traditional and folk medicines. In present study petroleum ether and ethanolic extracts of A. precatorius seeds are evaluated for reversal of androgen (testosterone by i.m route) induced alopecia in male albino wistar rats and compared to topical administration of standard antiandrogenic drug fi nasteride for 21 days. The results were refl ected from visual observation and histological study of several skin sections via various parameters as anagen to telogen ratio and follicle density/mm area of skin surface. The animal of group 1 who were treated with only testosterone became alopecic on visual observation. Animals of Group 2, 3 and 4 who were treated with fi nasteride, petroleum ether and ethanolic extract of seed respectively topically along with testosterone (i.m) did not developed alopecia. To investigate the mechanism of observed activity, in vitro experiments were performed. Inhibition of 5α-reductase activity by extracts and fi nasteride suggest that they reversed androgen induced alopecia by inhibiting conversion of testosterone to dihydrotestosterone (potent androgen responsible for androgenic alopecia). So it may be concluded that petroleum ether and ethanolic extract of A. precatorius seed posses anti androgenic alopecia activity due to inhibition of 5α-reductase enzyme.

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17.beta.-(N-tert-Butylcarbamoyl)-4-aza-5.alpha.-androstan-1-en-3-one Is an Active Site-Directed Slow Time-Dependent Inhibitor of Human Steroid 5.alpha.-Reductase 1

Cited by 54 publications

References 23 publications

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

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

GABRA2 Alleles Moderate the Subjective Effects of Alcohol, Which are Attenuated by Finasteride

Effect of petroleum ether and ethanol fractions of seeds of Abrus precatorius on androgenic alopecia

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