Trends in Endocrinology & Metabolism
The backdoor pathway to dihydrotestosterone
Section snippets
The pathway to androstanediol in testes of tammar wallaby pouch young
Androstanediol can be synthesized in testis from T [2], but experiments with immature rat testis indicated another pathway for androstanediol synthesis that did not involve the conventional intermediates AD and T [6]. To characterize this pathway, pouch young testes have been incubated with [3H]progesterone and the metabolites identified by thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) (Figure 1, Box 1). Progesterone is metabolized rapidly to
Androstanediol synthesis in immature mouse testis
Although T is the principal 19-carbon product of adult mouse and rat testes, androstanediol is the principal 19-carbon product of immature mouse testes [4] and adult rodent testes under gonadotropin suppression. However, it was not known whether androstanediol derives from the 3α-reduction of DHT in the testis or by an alternate pathway; neither was it known whether androstanediol is synthesized in the fetal mouse testes. Although Pdiol had been identified as a progesterone metabolite in
In vitro studies of human enzymes with 5α-reduced substrates
Using human recombinant CYP17 expressed in yeast microsomes [8], the 5α-reduced 21-carbon steroids 5α-pregnan-3,20-dione and 5α-prenan-3α-ol-20-one have been shown to be excellent substrates for the 17α-hydroxylase activity of human CYP17 [13]. Furthermore, Pdiol is an better substrate for the 17,20-lyase activity of human CYP17 than 17α-hydroxypregnenolone, with a comparable Km and 10-fold higher Vmax. In addition, the conversion of Pdiol to androsterone is stimulated only three-fold by
Factors that govern relative flux through the conventional and backdoor pathways
By comparing the results of studies using mouse and tammar wallaby testes, some general principles emerge that explain the variations in flux through the various pathways to androstanediol and DHT. The relative abundance of CYP17 compared with 5α-reductase (presumably always type 1) and the efficiency with which CYP17 from different species catalyzes the 17,20-lyase reaction with Δ4 steroids appear to be the two key factors that regulate the partitioning of steroid flux to 19-carbon steroids
Conclusions
The 5α-reduction of T is not the only biosynthetic pathway to DHT. DHT can be formed efficiently from the 5α-reduced 21-carbon precursor Pdiol via the pathway(s) progesterone→→→Pdiol→androsterone→androstanediol→DHT, which is the principal route to DHT in the testis of the tammar wallaby pouch young during sexual differentiation. The relevant human steroidogenic enzymes perform all the chemical transformations contained in this route to DHT.
The backdoor pathway might provide the basis for some
Acknowledgements
I am indebted to my colleagues in Dallas and Australia, particularly Jean Wilson, who participated in the studies referenced in this review that led to the elucidation of this pathway. Their helpful discussions and insightful comments have been essential in developing our thoughts about this topic. This work was supported by NIH grant R21DK56642 and grant I-1493 from the Robert A. Welch Foundation.
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