Testosterone metabolism to 5?-dihydrotestosterone and synthesis of sebaceous lipids is regulated by the peroxisome proliferator-activated receptor ligand linoleic acid in human sebocytes

Q1 · MEDICINE

Article

Author: C.C. Zouboulis ; E. Makrantonaki

BACKGROUNDDespite the clinical evidence that androgens stimulate sebaceous lipids, androgens in vitro have shown no similar effects. This contradiction led to the assumption that cofactors may be required for lipid regulation and peroxisome proliferator-activated receptor (PPAR) ligands were suggested to be adequate candidates.OBJECTIVESThe influence of testosterone and linoleic acid, a PPAR ligand, as single agents and in combination with of LY191704, a 5alpha-reductase type I inhibitor, was examined on 5alpha-dihydrotestosterone (5alpha-DHT) synthesis and lipid content in human SZ95 sebocytes.METHODSCell proliferation and viability were measured by the 4-methylumbelliferyl heptanoate fluorescence assay and by the Boehringer Lactate Dehydrogenase Assay kit, respectively. 5alpha-DHT enzyme-linked immunosorbent assay was used for the detection of 5alpha-DHT synthesis in cell supernatants after treatment, whereas lipid production was documented by means of the Nile red lipid microassay and fluorescence microscopy.RESULTSTestosterone promoted 5alpha-DHT synthesis (P < 0.001), whereas linoleic acid increased sebaceous lipids (P < 0.001). The combination of testosterone and linoleic acid exhibited a synergistic effect on the synthesis of 5alpha-DHT (P < 0.01 vs. testosterone) and sebaceous lipids (P < 0.01 vs. linoleic acid). Furthermore, LY191704 reduced 5alpha-DHT and sebaceous lipid levels (P < 0.01 and P < 0.001 in comparison with testosterone/linoleic acid, respectively). Cell proliferation and viability remained unchanged under treatment with all compounds tested.CONCLUSIONSThese data suggest a catalytic effect of PPAR ligands on cellular testosterone activation by 5alpha-reduction and the importance of the latter for the regulation of sebaceous lipids.

01 Dec 2002·The Journal of Clinical Endocrinology & MetabolismQ2 · MEDICINE

Human Osteoblast-Like Cells Express Predominantly Steroid 5α-Reductase Type 1

Q2 · MEDICINE

Article

Author: Maritta Feix ; Hans Eckart Schaefer ; Lutz Wolf ; David W. Russell ; Hans Udo Schweikert ; Sedika Issa ; Doris Schnabel

In previous studies we established that human bone and human osteoblast-like cells (hOB cells) cultured from bone express 5alpha-reductase (5alpha-R) activity, as demonstrated by the conversion of testosterone and androstenedione to their corresponding 5alpha-reduced metabolites, 5alpha-dihydrotestosterone (DHT) and 5alpha-androstanedione. Two 5alpha-R isozymes (types 1 and 2) have been identified in various tissues. As their nature in bone is unknown, we investigated which isozymes were expressed in first passage hOB cells cultured from bone specimens obtained from six donors (five women and one man). For comparison, 5alpha-reductase isozyme expression in genital skin fibroblasts cultured from foreskin of three males was determined. Pharmacological and biochemical studies using selective inhibitors of the 5alpha-R isozymes were performed, and gene expression was assessed by RT-PCR. In hOB cells, LY191704, a potent nonsteroidal selective inhibitor of 5alpha-R type 1, and the 4-azasteroid 17beta-(N,N,-diethyl-carbamoyl)-4-methyl-4-aza-5alpha-androstan-3-one (a dual inhibitor of 5alpha-R types 1 and 2) inhibited 5alpha-R activity with a 50% inhibitory concentration (IC(50)) of approximately 4 nM. Finasteride, a selective inhibitor of 5alpha-R type 2, blocked 5alpha-R activity with an IC(50) of approximately 60 nM. The IC(50) of progesterone, a physiological substrate for 5alpha-R, was approximately 200 nM. In genital skin fibroblasts, LY191704 inhibited 5alpha-R with an IC(50) of more than 5000 nM, whereas finasteride and 17beta-(N,N,-diethyl-carbamoyl)-4-methyl-4-aza-5alpha-androstan-3-one effectively inhibited 5alpha-R with IC(50) of approximately 4 nM. Experiments to determine 5alpha-reductase activity in homogenates of hOB cells as a function of pH showed very low activity at pH 5.5, but a broad shoulder of activity from pH 6.0-9.0, which was not inhibited by finasteride, but was nearly completely blocked by LY191704. RT-PCR revealed that 5alpha-R type 1 and 2 mRNAs were expressed in both bone and genital skin fibroblasts. Based on our pharmacological and biochemical studies, it appears that 5alpha-R activity in hOB cells is catalyzed predominantly by the type 1 rather than the type 2 isozyme. This expression pattern is in contrast to that in genital skin fibroblasts, where the activity of the type 2 isozyme prevails. As in most androgen target tissues DHT is biologically more active as an androgen than testosterone, DHT is formed in bone by 5alpha-R type 1 action from circulating testosterone, and bone cells also express the androgen receptor, local DHT production may play a physiological role in human bone homeostasis.

01 Oct 2000·Journal of Medicinal ChemistryQ1 · MEDICINE

Benzo[c]quinolizin-3-ones: A Novel Class of Potent and Selective Nonsteroidal Inhibitors of Human Steroid 5α-Reductase 1

Q1 · MEDICINE

Article

Author: Mancina, Rosa ; Hardy, Kimber ; Guarna, Antonio ; Comerci, Alessandra ; Scarpi, Dina ; Machetti, Fabrizio ; Occhiato, Ernesto G. ; Serio, Mario ; Danza, Giovanna

The synthesis and biological evaluation of a series of novel, selective inhibitors of isoenzyme 1 of human 5alpha-reductase (5alphaR) (EC 1.3.99.5) are reported. The inhibitors are 4aH- (19-29) or 1H-tetrahydrobenzo[c]quinolizin-3-ones (35-47) bearing at positions 1, 4, 5, and 6 a methyl group and at position 8 a hydrogen, methyl group, or chlorine atom. All these compounds were tested toward 5alphaR-1 and 5alphaR-2 expressed in CHO cells (CHO 1827 and CHO 1829, respectively) resulting in selective inhibitors of the type 1 isoenzyme, with inhibitory potencies (IC(50)) ranging from 7.6 to 9100 nM. The inhibitors of the 4aH-series, having a double bond at position 1,2, were generally less active than the corresponding inhibitors of the 1H-series having the double bond at position 4,4a on the A ring. The presence of a methyl group at position 4 (as in compounds 39-40 and 45-47), associated with a substituent at position 8, determined the highest inhibition potency (IC(50) from 7.6 to 20 nM). Compounds 39 and 40, having K(i) values of 5.8+/-1.8 and 2.7+/-0.6 nM, respectively, toward 5alphaR-1 expressed in CHO cells, were also tested toward native 5alphaR-1 in human scalp and 5alphaR-2 in human prostate homogenates, in comparison with finasteride and the known 5alphaR-1-selective inhibitor LY191704, and their mechanism of inhibition was determined. They both inhibited the enzyme through a reversible competitive mechanism and again were selective inhibitors of 5alphaR-1 with IC(50) values of 41 nM. These specific features make these inhibitors suitable candidates for further development as drugs in the treatment of DHT-dependent disorders such as acne and androgenic alopecia in men and hirsutism in women.

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