Regulation of pregnenolone metabolism

The first product of the cholesterol side chain process, pregnenolone, which is biologically inactive, is further metabolised by enzymes present in the endoplasmic reticulum. Much has been learned about the primary structure and the biosynthesis of various P450 enzymes after application of new techniques such as protein chemistry and molecular biology (reviewed by Miller 1988). This can be illustrated for enzyme activities that convert C21-pregnenolone to C19-steroids. It was previously thought that 17-hydroxylase and C17,20-lyase activity reside in separate enzymes which could be differentially regulated by hormones with predominant 17-hydroxylation in the adrenal and C17,20-lyase activity in the testis (Smals et al. 1980; Rommerts and Brinkmann 1981). However, both enzyme activities occur in a single protein, P450C17, coded by one gene CYP 17 (Zuber et al. 1986) and the differential expression of enzyme activities in the testis and the adrenal depends on the micro-environment of the enzyme in the endoplasmic reticulum. Mutations in the P450C17 protein can also favour a particular enzyme activity (van den Akker et al. 2002). The formation of androgens in the testis is caused by relatively high reduction power owing to high levels of P450 reductase and cytochrome b5 (Hall 1991). Protein phosphatase activities may play a role in the physiological regulation of the P450C17 activity (Zhang etal. 1995; Pandey etal. 2003).

In the testis, the synthesis of P450C17 is under the control of LH, via cAMP stimulation of CYP17 gene expression (Payne and O'Shauhgnessy 1996). This protein

Metabolism of pregnenolone in endoplasmic reticulum.

A16-androgens

Metabolism of pregnenolone in endoplasmic reticulum.

kinase A-mediated synthesis of P450C17 can be inhibited by antimullerian hormone (AMH) (Laurich et al. 2002). Deficiency of P450C17 is rare but a few cases of individuals with female phenotypes have been reported (Monno et al. 1993; van den Akker etal. 2002). The degradation of the enzyme can be enhanced in the presence of elevated levels of steroids by oxygen-mediated damage. Although this steroid-mediated inactivation has been shown to occur in vitro, it is unknown whether this process plays a role in the regulation of enzyme activity in vivo at low oxygen tension (Payne etal. 1985).

The presence of many steroid-converting enzymes allows many different pathways to convert pregnenolone into testosterone (see Figure 1.1). Depending on whether pregnenolone is converted initially by the 3^-hydroxysteroid dehydrogenase/A5-A4-isomerase complex or the P450C17 enzyme, a A4- or A5-pathway predominates. In the human testis most of the steroids are formed via the A5-pathway with dehydroepiandrosterone (DHEA) as the first C19 intermediate (Weusten et al. 1987b) (see Figure 1.3). The enzyme 3^-hydroxysteroid dehydrogenase/A5-A4-isomerase (3SHSD) catalyses the conversion of A5-3^-hydroxysteroids to A4-3-ketosteroids, an essential step in the biosynthetic pathway. The dehydrogenase and isomerase activities are catalysed by one protein coded by one gene (Lachane etal. 1990). Although the two enzyme activities are carried out by one single protein, separate sites on the molecule mediate the specific enzyme activities (Luu-The etal. 1991). Different isoforms of this enzyme are expressed in steroidogenic tissues but also in non-steroidogenic tissues. In the human testis the type II iso-enzyme is expressed with almost equal affinity for dehydroepiandros-terone and pregnenolone. Several point mutations of the gene that affect intracellular location and affinity for the substrate have been identified (Rheaume etal. 1995).

The final step in the biosynthetic pathway of testosterone is the reduction of the 17-keto-group by the 17^-hydroxysteroid dehydrogenase (17^HSD). This enzyme activity is represented by five different isoforms that are ubiquitously present in many tissues (Andersson and Moghrabi 1997). An interesting feature of 17^HSD type 2 is that the enzyme also possesses 20aHSD activity. In the testis the type 3 isoform is present, mainly in the Leydig cells. Although generally present in the body, deficiency of the testicular activity of 17^HSD accounts for most defects in testosterone biosynthesis in the human (Geissler et al. 1994; Labrie et al. 1997). When all steroid-converting activities are taken together, the pregnenolone-converting enzymes present in the smooth endoplasmic reticulum function in close cooperation and act as a metabolic trap for pregnenolone, released by the mitochondria.

This enzyme system is not capable of converting all pregnenolone into testosterone. Therefore it acts as the rate-limiting step for the ultimate production of androgens. Since the enzyme activities are differentially regulated, they play an important role in determining the output of testosterone, especially during development. Thus the normal testis produces many intermediates in addition to testosterone. Although these steroids are not androgens, they represent secretion products and they may have alternative functions. This must be kept in mind when only testosterone substitution therapy is applied for treatment of hypogonadism.

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