5α-reductase expression in the human prostate and the effect of Permixon® on isoenzyme activity

• Main Author: Bayne, Colin William
• Published: University of Edinburgh 1998
• Subjects: 616.994
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.641408

The expression, activity and control of 5α-reductase isoenzymes in human prostate and in various models of the prostate were examined along with the effect of the phytotherapeutic agent Permixon<SUP>®</SUP> on the activity of the expressed isoenzymes. Attempts were also made to identify the mechanism(s) which controls the expression of 5α-reductase type II in the epithelial cells. Fractionation of fibroblast conditioned medium size exclusion spin columns and ion exchange HPLC, demonstrated that an anionic protein of approximately 10kD in size, produced by protate fibroblast cells, induced a stimulation of the expression of 5α-reductase type II in primary cultured epithelial cells; Enzyme expression was reversed in the absence of this factor. The role of the 5α-reductase isoenzymes in the prostate is somewhat controversial with no clear reason being elucidated for the expression of two isoenzymes which appear to have the same function. However, by analysing the metabolites of testosterone, it was possible to identify separate and distinct roles for the isoenzymes within the prostate. Cells expressing only 5α-reductase type I demonstrate high levels of androstenedione following metabolism of testosterone and very low levels of DHT. Cells expressing both isoenzymes, demonstrate much higher levels of DHT and lower levels of androstendedione. The implication from this data is that 5α reductase type I has a higher affinity for androstenedione than for testosterone whereas the type II enzyme has a higher affinity for testosterone. This would suggest that these isoenzymes are responsible for two separate pathways for the metabolism of testosterone to DHT in the human prostate gland. With the development of a BPH model which expresses both isoforms of 5α-reductase and secretes PSA, the opportunity arose for investigation into the action of Permixon<SUP>®</SUP> on 5α-reductase and PSA. Permixon<SUP>®</SUP> demonstrated an ability to inhibit the action of both isoforms of 5α-reductase without having any effect on androgen sensitive processes such as PSA secretion and androgen induced growth. Electromicroscopy indicated that Permixon<SUP>®</SUP> has a disruptive effect on prostate derived cell membranes but has no similar effect on non-prostate derived cells.