Disease relevance of EPIANDROSTERONE

• The ratio of androsterone to tetrahydrocortisol, an index of the aging process, was significantly lower in a breast cancer group than in a normal group at both premenopausal and postmenopausal stages [1].
• Moreover, the change in severity of decreased sexual interest correlated significantly with the change in CSF androsterone levels between testosterone replacement and hypogonadism (r = -0.68; P<.05) [2].
• 3alpha-hydroxysteroid dehydrogenase/carbonyl reductase (3alpha-HSD/CR) from Comamonas testosteroni, a short chain dehydrogenase/reductase, catalyzes the oxidation of androsterone with NAD+ to form androstanedione and NADH [3].
• Surprisingly, when the recombinant protein was expressed and purified from Escherichia coli, the enzyme did not oxidize androsterone when measured spectrophotometrically, an activity previously assigned to recombinant type 2 3alpha-HSD using this assay [4].
• Recent data have provided evidence that androsterone (Ao) metabolism is exaggerated in acne and serum metabolites of Ao differentiate between acne and hirsutism in hyperandrogenic women [5].

Psychiatry related information on EPIANDROSTERONE

• These findings indicate that 7beta-hydroxy epiandrosterone has powerful cytoprotective effects suggesting that (a) this neurosteroid may have therapeutic potential in various neurodegenerative conditions such as Alzheimer's disease, and (b) 7beta-hydroxy steroids may constitute a novel class of endogenous neuroprotective agents [6].

High impact information on EPIANDROSTERONE

• The basal accumulation of androsterone (the major androgenic steroid), synthesized by whole ovarian dispersates from immature rats, remained unchanged following treatment with TNF alpha (30 ng/ml) alone [7].
• The cumulative results are consistent with a rapid equilibrium random-order sequential kinetic mechanism for the glucuronidation of testosterone by purified 17 beta-hydroxysteroid UDP-glucuronosyltransferase and of androsterone by purified 3 alpha-hydroxysteroid UDP-glucuronosyltransferase [8].
• Transfection of UDPGTr-4 cDNA into COS cells resulted in the glucuronidation of etiocholanolone, androsterone, and lithocholic acid in a transient expression assay [9].
• Basal androsterone production was not changed by incubation with IGF-I (30 ng/ml) [10].
• In the group of 42 PCOS subjects, measures of 5alpha/5beta reduction were positively correlated with the homeostasis model insulin resistance index (HOMA-R): alpha-THF/THF and HOMA-R (r = 0.34; P = 0.03), androsterone/etiocholanolone and HOMA-R (r = 0.32; P = 0.04), and total 5alpha /total 5beta and HOMA-R (r = 0.37; P = 0.02) [11].

Chemical compound and disease context of EPIANDROSTERONE

• Clinical observations have shown that hypercholesterolemia is associated with abnormal androgen metabolism, viz. an increased excretion of etiocholanolone (E) relative to androsterone (A) [12].
• Because of similarities in the relaxation of BCA to hypoxia (Po(2) = 8-10 Torr) and inhibitors of the pentose phosphate pathway (PPP) including 6-aminonicotinamide and epiandrosterone, we measured NADPH and NADP and found that hypoxia caused NADPH oxidation (decreased NADPH/NADP) [13].
• Little suppression of this behaviour was seen when the pseudopregnant rats were treated with progesterone or androsterone whereas treatment with dihydrotestosterone resulted in a significant inhibition of lordosis behavior [14].
• An androsterone D-lactam steroidal ester, the 3beta-hydroxy-13alpha-amino-13,17-seco- 5alpha-androstan-17-oic-13,17-lactam, p-bis(2-chloroethyl)amino phenyl acetate (lactandrate) was synthesized and tested for antitumor activity against six human breast cancer cell lines in vitro and against two murine and one xenograft mammary tumors in vivo [15].

Biological context of EPIANDROSTERONE

• Translation of the cDNA sequence of clone rlug 23, the longest member of class 4, allowed determination of the complete amino acid sequence of androsterone UDPGT [16].
• Age and sex influences were observed only with respect to the androsterone/etiocholanolone (A/E) ratio; a sex difference in diol metabolite formation was not observed [17].
• Concentrations are similar to those estimated by mass spectrometry and protein binding assays, except for androsterone which has not previously been measured in this context [18].
• These results provide evidence that androsterone GT and bilirubin GT are located on different chromosomes [19].
• Single- and multiple-turnover experiments for androsterone oxidation showed that while the wild-type enzyme demonstrated a k(lim) and burst kinetics consistent with slow product release, the W227A and F118A mutants eliminated this kinetic profile [20].

Anatomical context of EPIANDROSTERONE

• Using a specific anti-UGT2B17 antibody, the expression of this androsterone-conjugating UGT enzyme was found exclusively in basal cells of the epithelium [21].
• The results of this study also provide evidence that differences in the content of 3 alpha-hydroxysteroid UDP-glucuronosyltransferase within hepatocytes account for genetically determined variations in the rates at which androsterone and certain other xenobiotics are glucuronidated in livers of Wistar rats [22].
• Pulmonary arterial endothelial cells produced the same metabolites of [3H]androsterone (0.083 microM), with the exception of the polar compounds [5 alpha-androstane-3,17-dione (1.3 pmol mg-1 protein h-1), isoandrosterone (0.1 pmol mg-1 protein h-1), 5 alpha-DHT (0.2 pmol mg-1 protein h-1), and 3 alpha-diol (0.2 pmol mg-1 protein h-1)] [23].
• Protection against inflammatory neurodegeneration and glial cell death by 7beta-hydroxy epiandrosterone, a novel neurosteroid [6].
• Foster-feeding experiments showed that breast milk did not alter the genetically determined expression of androsterone UDP-glucuronosyltransferase activity in Wistar rats [24].

Associations of EPIANDROSTERONE with other chemical compounds

• However, after oral DHEA, PCOS women had significantly higher increases in serum 5 alpha-dihydrotestosterone (P < 0.01), its main metabolite androstanediol glucuronide (P < 0.05), and the 5 alpha-reduced urinary androgen metabolite androsterone (P < 0.05) [25].
• In the control group, mean (+/-SE) d 1 and 7 excretion rates for testosterone, androsterone, etiocholanolone, and dihydrotestosterone were 3 +/- 1, 215 +/- 26, 175 +/- 26, and 0.4 +/- 0.1 microg/h, respectively [26].
• However, mutation of the serine residue at position 121 of UGT2B17 to a tyrosine, as found in UGT2B15, abolished the ability of UGT2B17 to conjugate androsterone at the 3alpha position, but still retained activity for dihydrotestosterone and 5alpha-androstane-3alpha, 17beta-diol, which have an OH-group at the 17beta position [27].
• The three major urinary androgen metabolites, dehydroepiandrosterone (DHEA), androsterone (ANDRO), and aetiocholanolone (AETIO) were measured in 1,484 volunteer women between 29 and 60 years of age on the island of Guernsey from 1962-1967 [28].
• Effects of steroid hormones and xenobiotics on the pubertal development of UDP-glucuronosyltransferase activities towards androsterone and 4-nitrophenol in Wistar rats [24].

Gene context of EPIANDROSTERONE

• Nuclear magnetic resonance spectroscopy demonstrated the direct binding of androsterone to purified human FXR (hFXR) ligand-binding domain (LBD) protein, resulting in the recruitment of steroid receptor coactivator protein-1 (SRC-1) coactivator peptide [29].
• In mouse AML-12 hepatocytes, chenodeoxycholic acid (CDCA) or androsterone induced SHP expression with a similar kinetic pattern [29].
• Of the estrogenic compounds tested, UGT2B7 catalyzed the glucuronidation of estriol at rates comparable to those determined for androsterone [30].
• Human dehydroepiandrosterone sulfotransferase (DHEA-ST) catalyzes the sulfonation of DHEA, cholesterol, pregnenolone as well as androsterone [31].
• Screening for RNA expression by RT-PCR confirmed the absence of UGT2B4 and UGT1A6 and showed expression of UGT2B7, a hepatic isoform shown to glucuronidate androsterone, in all intestinal segments [32].

Analytical, diagnostic and therapeutic context of EPIANDROSTERONE

• Hybridisation of these probes to northern blots of total RNA prepared from the livers of normal and genetically deficient Wistar rats identified the cDNA in class 4 with androsterone UDPGT [16].
• Such temporally related behavior requires rapid production and removal of both 17-ketosteroids, processes which have been confirmed by tracer studies where it has been shown that in a two compartment system, androsterone has a t1/2 of 25 +/- 9 min for the fast component and metabolic clearance rate of 4050 +/- 1315 L per day (n = 10) [33].
• To identify the individual A-LCFE, breast tumor homogenates were incubated with androsterone, then submitted to solvent extraction, Celite chromatography, high pressure liquid chromatography and OH- negative chemical ionization mass spectrometry [34].
• The aim of the present study was to establish whether treatment with 7beta-hydroxy epiandrosterone has a neuroprotective effect in animal models of Alzheimer's disease (AD) lesions [6].
• Site-directed mutagenesis of the hFXR-LBD defined amino acids Asn354 and Ser345 as critical for differential species sensitivity to CDCA and androsterone, respectively [29].

References