Oxidative metabolism of dehydroepiandrosterone (DHEA) and biologically active oxygenated metabolites of DHEA and epiandrosterone (EpiA) – Recent reports

Kihel, Laïla El

doi:10.1016/j.steroids.2011.09.008

Cited by 48 publications

(31 citation statements)

References 180 publications

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“…Dehydroepiandrosterone (DHEA) is the precursor of androgens (and estrogens) and leads via enzymes such as 5α-reductase to epiandrosterone, androsterone, testosterone, and other steroids; 4-androstene-3beta,17beta-diol disulfate 1 and 2 also are known as androstenediols and are intermediates in the synthesis of testosterone from DHEA. Dehydroepiandrosterone sulfate (DHEA-S) is a metabolite of DHEA, but also can be back-converted to DHEA 11 . Testosterone and di-hydro testosterone have the highest potency as androgens, and DHEA, epiandrosterone, and androsterone are relatively weak androgens.…”

Section: Discussionmentioning

confidence: 99%

A Metabolome-Wide Study of Dry Eye Disease Reveals Serum Androgens as Biomarkers

2017

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PurposeTo test the association between serum metabolites and dry eye disease (DED) using a hypothesis-free metabolomics approach.DesignCross-sectional association study.ParticipantsA total of 2819 subjects from the population-representative TwinsUK cohort in the United Kingdom, with a mean age of 57 years (range, 17–82 years).MethodsWe tested associations between 222 known serum metabolites and DED. All subjects underwent nontargeted metabolomic analysis of plasma samples using gas and liquid chromatography in combination with mass spectrometry (Metabolon Inc., Durham, NC). Dry eye disease was defined from the validated Short Questionnaire for Dry Eye Syndrome (SQDES) as a previous diagnosis of DED by a clinician or “often” or “constant” symptoms of dryness and irritation. Analyses were performed with linear mixed effect models that included age, BMI, and sex as covariates, corrected for multiple testing.Main Outcome MeasuresPrimary outcome was DED as defined by the SQDES, and secondary outcomes were symptom score of DED and a clinical diagnosis of DED.ResultsPrevalence of DED as defined by the SQDES was 15.5% (n = 436). A strong and metabolome-wide significant association with DED was found with decreased levels of the metabolites androsterone sulfate (P = 0.00030) and epiandrosterone sulfate (P = 0.00036). Three other metabolites involved in androgen metabolism, 4-androsten-3beta,17beta-diol disulfate 1 and 2, and dehydroepiandrosterone sulfate, were the next most strongly associated of the 222 metabolites, but did not reach metabolome-wide significance. Dryness and irritation symptoms, as opposed to a clinical diagnosis, were particularly strongly associated with decreased androgen steroid metabolites, with all reaching metabolome-wide significance (androsterone sulfate, P = 0.000000029; epiandrosterone sulfate, P = 0.0000040; 4-androsten-3beta,17beta-diol disulfate 1, P = 0.000016; 4-androsten-3beta,17beta-diol disulfate 2, P = 0.000064; and dehydroepiandrosterone sulfate, P = 0.00011). Of these 5 androgens, epiandrosterone sulfate (P = 0.0076) was most associated with 2-year incidence of clinician-diagnosed DED. In addition, we found decreased glycerophosphocholines to be associated with DED, although not at metabolome-wide significance.ConclusionsThis hypothesis-free metabolomic approach found decreased serum androgens to be highly associated with DED and adds important evidence to the growing body of research that links androgens to ocular surface disease and DED.

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Section: Discussionmentioning

confidence: 99%

A Metabolome-Wide Study of Dry Eye Disease Reveals Serum Androgens as Biomarkers

2017

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“…DHEA action is primarily exerted through its metabolites [42], being testosterone one of the most well-known and bestcharacterized. In fact, DHEA can be converted to androstenedione via the enzyme 3b-hydroxysteroid dehydrogenase (3b-HSD) and subsequently to testosterone by the enzyme 17b-hydroxysteroid dehydrogenase (17b-HSD) [22].…”

Section: Discussionmentioning

confidence: 99%

Dehydroepiandrosterone and 7-oxo-dehydroepiandrosterone in male reproductive health: Implications of differential regulation of human Sertoli cells metabolic profile

Dias

Alves

Almeida

et al. 2015

The Journal of Steroid Biochemistry and Molecular Biology

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“…Even though the mechanistic insights of CYP106A2 steroid hydroxylation remain elusive, its production of human DHEA metabolites is highly interesting, because 7-oxygenated DHEA derivatives have been discussed as neuroprotective, immune-modulatory and anti-inflammatory agents [35]. Besides, hydroxylated steroids are highly interesting lead compounds for drug development targeting P450 enzymes, especially CYP19A1 (aromatase) which is involved in the formation of post-menopausal breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Steroid conversion with CYP106A2 – production of pharmaceutically interesting DHEA metabolites

2014

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BackgroundSteroids are lipophilic compounds with a gonane skeleton and play an important role in higher organisms. Due to different functionalizations - mainly hydroxylations - at the steroid molecule, they vary highly in their mode of action. The pharmaceutical industry is, therefore, interested in hydroxysteroids as therapeutic agents. The insertion of hydroxyl groups into a steroid core, however, is hardly accomplishable by classical chemical means; that is because microbial steroid hydroxylations are investigated and applied since decades. CYP106A2 is a cytochrome P450 monooxygenase from Bacillus megaterium ATCC 13368, which was first described in the late 1970s and which is capable to hydroxylate a variety of 3-oxo-delta4 steroids at position 15beta. CYP106A2 is a soluble protein, easy to express and to purify in high amounts, which makes this enzyme an interesting target for biotechnological purposes.ResultsIn this work a focused steroid library was screened in vitro for new CYP106A2 substrates using a reconstituted enzyme assay. Five new substrates were identified, including dehydroepiandrosterone and pregnenolone. NMR-spectroscopy revealed that both steroids are mainly hydroxylated at position 7beta. In order to establish a biotechnological system for the preparative scale production of 7beta-hydroxylated dehydroepiandrosterone, whole-cell conversions with growing and resting cells of B. megaterium ATCC1336 the native host of CYP1062 and also with resting cells of a recombinant B. megaterium MS941 strain overexpressing CYP106A2 have been conducted and conversion rates of 400 muM/h (115 mg/l/h) were obtained. Using the B. megaterium MS941 overexpression strain, the selectivity of the reaction was improved from 0.7 to 0.9 for 7beta-OH-DHEA.ConclusionsIn this work we describe CYP106A2 for the first time as a regio-selective hydroxylase for 3-hydroxy-delta5 steroids. DHEA was shown to be converted to 7beta-OH-DHEA which is a highly interesting human metabolite, supposed to act as neuroprotective, anti-inflammatory and immune-modulatory agent. Optimization of the whole-cell system using different B. megaterium strains lead to a conversion of DHEA with B. megaterium showing high selectivity and conversion rates and displaying a volumetric yield of 103 mg/l/h 7beta-OH-DHEA.

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Oxidative metabolism of dehydroepiandrosterone (DHEA) and biologically active oxygenated metabolites of DHEA and epiandrosterone (EpiA) – Recent reports

Cited by 48 publications

References 180 publications

A Metabolome-Wide Study of Dry Eye Disease Reveals Serum Androgens as Biomarkers

A Metabolome-Wide Study of Dry Eye Disease Reveals Serum Androgens as Biomarkers

Dehydroepiandrosterone and 7-oxo-dehydroepiandrosterone in male reproductive health: Implications of differential regulation of human Sertoli cells metabolic profile

Steroid conversion with CYP106A2 – production of pharmaceutically interesting DHEA metabolites

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