5a-Reductase and Its Inhibitors

15 May

Rainer Voegeli Department of Research and Development, Pentapharm Ltd., Basel, Switzerland  Christos C. Zouboulis Departments of Dermatology and Immunology, Dessau Medical Center, Dessau, Germany Peter  Elsner Department of Dermatology and Allergology, Friedrich-Schiller-University Jena, Jena, Germany

Thomas Schreier

Department of Research and Development, Pentapharm Ltd., Basel, Switzerland


5a-dihydrotestosterone (DHT) exerts a 2 to 10 times stronger androgen activity than testosterone. Thus,  this  steroid hormone was  supposed to play  a more  important role than  testosterone in many  androgen-dependent diseases such  as acne, hirsut- ism, androgenetic alopecia,  benign  prostatic hyperplasia, and  prostate carcinoma. DHT is converted from testosterone by the enzyme 5a-reductase. There are two iso- enzymes of 5a-reductase (types  1 and  2) that  differ  in their  localization within the body and even in the skin. Activity  of the type 1 isoenzyme predominates in sebac- eous  glands, where it may  be involved in regulation of sebum production. There- fore,   specific   inhibition  of  type   1  5a-reductase  may   represent  a  therapeutic approach to acne.  This review  refers  to the  features both  of 5a-reductases and  of their  inhibitors.


The androgenic provoked stimulation of sebum production plays  a crucial  role in the  pathogenesis of acne.  Although numerous factors  contribute to the  develop- ment  of acne,  the  requirement for androgens is absolute (1). Thiboutot et al. (2) and  Fritsch  et  al.  (3) demonstrated that  human skin  is  indeed a  steroidogenic tissue. The skin functions as an independent peripheral endocrine organ (4) expres- sing all the enzymes necessary for androgen synthesis and  catabolism. It can syn- thesize  cholesterol from   acetate   and   can  further  metabolize steroids  such   as dehydroepiandrosterone sulfate  into  potent androgens such  as  testosterone and DHT. DHT itself further induces enzymes such as 3a-hydroxysteroid dehydrogen- ase and  17b-hydroxysteroid dehydrogenase (5).

The skin  compartment responsible for both  the  initiation of steroidogenesis and  the  local  production of potent androgens seems  to be the  sebaceous gland. Therefore, selective  local interruption of this pathway can be of therapeutic benefit in androgen-mediated diseases of the skin and  allows  for effective  treatments (3).

Further  details  on  the   androgen  metabolism  in  the   skin   are   explicitly described in Chapter 7.

5a-REDUCTASE Historical Background

It was not until  1954 that  a series  of 5a-reduced steroids, produced from the incu- bation  of androst-4-ene-3,17-dione with  rabbit  liver  homogenate, was  recognized by paper chromatography. Two years  later,  DHT was  first identified as the  major metabolite of the incubation of testosterone with  rat liver homogenate. Both inde- pendent experiments indicated the presence of 5a-reductase in the liver tissues  of rabbits  and  rats. Since then, this membrane-bound enzyme has been demonstrated to be present in many  other  organs and  androgen-sensitive tissues of mammalian species   (6).  Subsequent  investigations  revealed  that   the  enzyme catalyzes the reduction of a variety of steroids, while  nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) is needed as an essential cofactor  (Fig. 1) (7).

The realization that 5a-reductase plays an important role in androgen metab- olism began  in the early  1960s, when in bioassays, DHT was demonstrated to be a more  potent androgen than  testosterone in the  prostate. Further studies revealed that  administration of radiolabeled testosterone led  to  an  accumulation of DHT in the nuclei  of ventral prostate cells. Moreover, DHT was shown to bind  preferen- tially  to  the  specific  nuclear androgen receptor in  target  organs. The  androgen receptor is a member of the steroid-thyroid-retinoid family of transcription regulat- ory  factors.  The  DHT-receptor complex interacts  with   specific  portions of  the genome  to  regulate  gene   activities. Developmental  studies  revealed  that   5a- reductase activity  in mammalian embryos was high in the primordia of the prostate and external genitalia prior  to their virilization but very low in Wolffian duct  struc- tures,  suggesting that  the enzyme was  crucial  for the development of the normal male  phenotype during embryogenesis. Taken  together, these  data  implied that conversion of testosterone to  DHT  by  5a-reductase was  a  critical  step  in  male sexual differentiation and focused attention on the role of 5a-reductase in androgen physiology and  pathophysiology (7).

Studies  in the 1970s and  1980s revealed that  the skin, in addition to the pros- tate, is rich in 5a-reductase. In this respect, it appeared very likely that 5a-reductase functions as an autocrine mediator in both the skin growth and  skin differentiation (8). In 1976, the  biochemical properties of 5a-reductase were  investigated in cell- free extracts  of fibroblasts cultured from genital  and nongenital skin of healthy sub- jects and  patients with  male  hermaphroditism. In these  experiments, two types  of

5a-reductase activities were  distinguished: one  detectable mainly in genital  skin with  an  optimal pH  of about  5.5 and  another with  an  optimal pH  between six

and  nine in all fibroblasts, cultured from normal and  mutant skin taken  from both genital   and   nongenital areas.   Patients with   congenital 5a-reductase  deficiency seemed to lack  the  former  enzyme only  (9). In contrast to type-2  isoenzyme, no human pathology with  a  deficiency or  mutation of  the  type  1 isoenzyme has been identified so far (10).

In   the   following,  attention  has   been   focused  on   molecular   biological approaches to identifying and  isolating 5a-reductase. In 1989, a cDNA  encoding a rat liver  5a-reductase was  isolated and  used  to identify a single  mRNA  species in both  liver  and  prostate of the  rat.  When  this  rat  5a-reductase cDNA was  used to screen cDNA libraries constructed from human prostate mRNA, a corresponding cDNA  was  isolated in 1990. However, when the  human cDNA  was  expressed in COS  cells,  the  5a-reductase activity  produced was  highest at  the  physiological pH  values,  and  not at 5.5 as deduced from  earlier  biochemical studies. Moreover, the enzyme showed different inhibitor specificity  than expected. As the gene encod- ing this cDNA was also normal in 5a-reductase-deficient individuals, it was again suggested in 1991 that there must  be at least 2 isoforms of human 5a-reductase (11), as already proposed by Moore and Wilson (12) by biochemical means in 1976. Later on, a second 5a-reductase gene was  also isolated from a human prostate genomic library.  This gene encoded a protein with 50% homology to the former  one. Accord- ingly,  these  enzymes were  designated as type  1 and  type  2 5a-reductase, respect- ively, in the order in which  they  were  cloned  (11).

Physiological Role

5a-reductase is the key enzyme in androgen metabolism. Altered enzyme function and/or  regulation are  responsible for numerous human pathologies. In humans, the  normal activity   of  5a-reductases routinely maintains testosterone-mediated biological  functions, such as anabolic actions  (muscle-mass increase, penis  enlarge- ment,  scrotum enlargement, and  vocal cords  enlargement), spermatogenesis (male sex drive and performance), and DHT-mediated effects, such as increased facial and body  hair,  scalp  hair  recession, acne, and  prostate enlargement (6).

The deficiency of 5a-reductase in males  results in incomplete differentiation of  the  external genitalia at  birth.  At  puberty, patients have  normal-to-elevated levels  of testosterone in plasma, and  virilization occurs,  but  the  prostate remains small  and  there  is no acne. Male pseudohermaphroditism is accompanied by low levels  of DHT. However, females  with  5a-reductase deficiency appear to have  no clinical  signs,  however, the  enzyme also  metabolizes other  4-ene-3-oxosteroids, such  as progesterone and  corticosterone. Abnormally, high  5a-reductase activity in humans results in excessively high  DHT  levels  in peripheral tissues,  which  is implicated in the pathogenesis of prostate carcinoma, benign prostatic hyperplasia, acne, hirsutism, and  androgenetic alopecia (6).

The exact physiological role of type 2 5a-reductase in tissues other than  pros- tate and  accessories of the external genitalia remains unknown, since these  organs do  not  appear to  be affected  by  the  genetic  absence  of this  isoenzyme or  by  its pharmacological inhibition and the women concerned have normal sexual develop- ment  and  are  fertile.  The physiological reasons and  the  factors  that  mediate this temporal pattern of expression are not  known. However, given  the role of andro- gens  in 5a-reductase regulation, it is intriguing to speculate that  the expression of one  gene  may  influence the  timing or expression level  of the  other:  type  2 isoen- zyme  had  a  priming effect  on  tissues,  such  as  the  prostate, skin  and  scalp,  on which  type  1 isoenzyme will act later  in life (13).

The androgen control of sebum production and the role of type 1 5a-reductase in  the  pathogenesis of  acne  are  confirmed by  the  following  data   and   clinical observations:

1.    Male  castrates produce less sebum than  normal males  and  they  do  not  have acne unless  testosterone is given.

2.    Androgen administration also  results in a significant increase in sebum pro- duction in women.

3.    Human sebaceous glands are rich in type  1 5a-reductase activity.

4.    Sebum  production is not detectable in subjects  with  complete androgen insen- sitivity  (13).

5.    Adult males with type 2 5a-reductase deficiency have sebum production scores identical to normal age-matched males.

6.    Males with benign prostatic hyperplasia treated with Finasteride (5 mg/day for one  year)  did  not  show   decreased sebum production, although the  serum

5a-DHT level was  lowered (14).

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