DHEA 1(University of Manchester)

Microbial transformation of dehydroepiandrosterone (DHEA, 1) using Penicillium griseopurpureum Smith and Penicillium glabrum (Wehmer) Westling has been investigated. Neither fungi had been examined previously for steroid biotransformation. One novel metabolic product of DHEA (1) transformed with P. griseopurpureum Smith, 15α-hydroxy-17a-oxa-d-homo-androst-4-ene-3,17-dione (5), was reported for the first time. The steroid products were assigned by interpretation of their spectral data such as (1)H NMR, (13)C NMR, IR, and HR-MS spectroscopy. P. griseopurpureum Smith was proven to be remarkably efficient in oxidation of the DHEA (1) into androst-4-en-3,17-dione (2). The strain was also observed to yield different monooxygenases to introduce hydroxyl groups at C-7α, -14α, and -15α positions of steroids. Preference for Baeyer-Villiger oxidation to lactonize D ring and oxidation of the 3β-alcohol to the 3-ketone were observed in both incubations. The strain of P. glabrum (Wehmer) Westling catalyzed the steroid 1 to generate both testololactone 3, and d-lactone product with 3β-hydroxy-5-en moiety 8. In addition, the strain promoted hydrogenation of the C-5 and C-6 positions, leading to the formation of 3β-hydroxy-17a-oxa-d-homo-5α-androstan-3,17-dione (9). The biotransformation pathways of DHEA (1) with P. glabrum (Wehmer) Westling and P. griseopurpureum Smith have been investigated, respectively. Possible metabolic pathways of DHEA (1) were proposed.

Numerous studies investigated the effects of pharmacological doses of DHEA in animals. Among protective effects, antiglucocorticoid potencies, triggering and modulation of immunity and anticancerous effects were reported. Because DHEA levels decrease in aging humans, this steroid has been assayed as replacement therapy in elderly volunteers without striking evidence for beneficial effects. Examination of the investigations carried out in animals lead to suspect that, rather than DHEA, its metabolites produced in tissues could be responsible for some of the observed effects. Known as the “mother steroid”, DHEA is a precursor for androgenic and estrogenic steroid hormones. In addition, DHEA is hydroxylated at the 7α position by the cytochrome P450 7B1 (CYP7B1), and the 7α-hydroxy-DHEA produced is a substrate for the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which converts it into 7β-hydroxy-DHEA. Both 7-hydroxylated metabolites were shown to favor the onset of immunity in mice and the activation of memory T cells in humans. Other DHEA and testosterone-derived metabolites, namely epiandrosterone and 5α-androstane-3β,17β-diol, are also substrates for the CYP7B1 and their 7α-hydroxylated products were also converted into the 7β epimer by the 11β-HSD1. When assayed at doses 104 lower than DHEA, 7β-hydroxy-epiandrosterone was shown to shift the prostaglandin metabolism patterns from prostaglandin E2 (PGE2) to PGD2 production, thus triggering the resolution of inflammation. In addition, 7β-hydroxy-epiandrosterone (1 nM) exerted the same effects as tamoxifen (1 μM) on the proliferation of MCF-7 and MDA-231 human breast cancer cells. These findings suggest that the observed effects of 7β-hydroxy-epiandrosterone could be mediated by estrogen receptors. This overview of recent research implies that DHEA does not act directly and that its effects are due to its metabolites when produced in tissues. Treatments with DHEA should take into account the target tissue abilities to produce the desired metabolites through the two key enzymes, CYP7B1 and 11β-HSD1.