In vitro metabolism of testosterone-4-14C and Δ4-androstene-3,17-dione-414C in human skin

Gomez, Edward C.; Hsia, S.L.

doi:10.1021/bi00841a004

Cited by 145 publications

(49 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The mean values (in liters/gram of serum protein) were, respectively, 1.56 +0.59 SE for testicular feminization syndrome cases (n = 6 determinations), 0.90 0.21 SE is 2 times higher than that originating from testosterone which enters the liver directly by the portal vein, whereas the yield of androstanediol arising from testosterone percutaneously applied is 2.5 times higher than that arising from testosterone injected in the peripheral circulation. These results are in agreement with in vitro data suggesting that a characteristic of cutaneous testosterone metabolism is the stereospecific reduction of the ring A leading to the formation of 5a-androstane steroids (18,19). The actual importance of testosterone metabolism by an organ as large as the skin is difficult to establish.…”

Section: Introductionsupporting

confidence: 85%

Studies on testosterone metabolism in subjects with testicular feminization syndrome

Mauvais-Jarvis¹,

Bercovici²,

Crépy³

et al. 1970

J. Clin. Invest.

115

View full text Add to dashboard Cite

A B S T R A C T The metabolism of radioactive testosterone simultaneously administered intravenously and either orally or percutaneously has been studied in seven patients with the syndrome of testicular feminization and compared with that of normal males and females. This investigation was carried out in order to determine the relative contribution to urinary 17-oxo and 17p-hydroxy androstane steroids of labeled testosterone, according to its mode of administration. In normal males the yields of urinary 5a-androstane-3a,17,-diol (androstanediol) originating from either an intravenous or a percutaneous dose of testosterone were respectively 3 and 6 times higher than those arising from an oral dose which perfuses the liver directly. These data indicate that in normal males, testosterone might be 5a-hydrogenated outside the liver. By contrast in patient with feminizing testes, because the contribution to androstanediol of radioactive testosterone is identical whatever its mode of administration, the extrahepatic 5a-reduction of this substrate seems very unlikely.The metabolic abnormalities observed in patients with testicular feminization syndrome may be reproduced in normal males by estrogen treatment. Nevertheless, the sensitivity of the patients to estrogen seems to be 10 times greater than that of normal males. This sensitivity was appreciated from the reduction of radioactive testosterone intravenously injected to urinary 17P-hydroxy-5a-androstan-3-one and androstanediol and also from the level of plasma binding for testosterone. This level was significantly higher (P < 0.05) in patients with feminizing testes than in normal males. The level increased dramatically after administration of a low dose of estrogen whereas this effect was not observed in normal males under the same experimental conditions.In light of these results the defect of extrahepatic 5a-reduction of testosterone observed in patients with Part of this work has been published as a preliminary communication (14).

show abstract

Section: Introductionsupporting

confidence: 85%

Studies on testosterone metabolism in subjects with testicular feminization syndrome

Mauvais-Jarvis¹,

Bercovici²,

Crépy³

et al. 1970

J. Clin. Invest.

115

View full text Add to dashboard Cite

show abstract

“…These metabolites are glucuronidated and excreted in bile and urine. Early studies of testosterone metabolism demonstrated that both 5a-and 5b-reduced metabolites were formed in the liver, while human skin and prostate had only 5a-reductase [20]. The expression of UGT2B19 transcripts in monkey liver is in agreement with the production of 5b-reduced steroids which would be glucuronidated and excreted from the body.…”

Section: Discussionmentioning

confidence: 85%

Molecular cloning, expression and characterization of a monkey steroid UDP‐glucuronosyltransferase, UGT2B19, that conjugates testosterone

Bélanger

Barbier

Hum

et al. 1999

European Journal of Biochemistry

View full text Add to dashboard Cite

Although enzymatic processes involved in the formation of active steroids are well known, less information is available about the enzymes responsible for the metabolism of these hormones. Moreover, the expression of these catabolic enzymes, which include UDP-glucuronosyltransferases, may play a role in the regulation of the level and action of steroid hormones in steroid target tissues. Previous studies have shown that the cynomolgus monkey contains high levels of circulating androgen glucuronides, indicating that it represents the best animal model to study the glucuronidation of steroids in extrahepatic tissues. Two cDNA libraries were constructed from monkey liver and prostate mRNA, and a novel UDP-glucuronosyltransferase UGT2B cDNA, UGT2B19, was isolated from both libraries. The UGT2B19 cDNA is 2108 bp in length and contains an open reading frame of 1584 bp encoding a protein of 528 residues. The UGT2B19 cDNA clone was transfected into HK293 cells and a stable cell line expressing UGT2B19 protein was established. The activity of UGT2B19 on 3a-hydroxy and 17b-hydroxy positions of steroids was demonstrated. The enzyme also conjugates xenobiotics including eugenol, 1-naphthol and p-nitrophenol. Kinetic analysis revealed that UGT2B19 glucuronidates steroids with K m values of 1.6, 2.6 and 4.3 mm for testosterone, etiocholanolone and 5b-androstane-3a,17b-diol, respectively. UGT2B19 transcript was detected, by specific reverse transcriptase-PCR analysis in the liver, ovary, prostate, colon, spleen, kidney, pancreas, brain, cerebellum, mammary gland and epididymis. The molecular characterization of simian UGT2B19 demonstrates relevance of using monkey as an animal model to study and understand steroid glucuronidation in extrahepatic target tissue.Keywords: cynomolgus monkey; androgen conjugation; steroid metabolism; extrahepatic tissue; phase II enzymes.To date more than 18 different UDP-glucuronosyltransferase enzymes have been isolated in humans and are classified into two families, UGT1 and UGT2, based on the homology of the amino acid sequence [1]. Less than 50% identity exists between these two families. The isoforms of the UGT1 family are encoded by a single gene locus which is composed of at least 12 different first exons and four common exons (exons 2±5) [2]. The UGT2 family is comprised of separate genes which share the same organization of six exons and five introns [3,4] . The UGT1 family are mainly active on xenobiotics but also demonstrate activity on endogenous compounds such as bilirubin, thyroid hormones and steroids. UGT2B enzymes are active on xenobiotics but the main activity is on steroids and bile acids.In humans, the plasma contains significant levels of steroid metabolites in the form of glucuronide conjugates. It has been suggested that the plasma levels of 5a-reduced C19 steroid glucuronides, androsterone-glucuronide and 5a-androstane3a,17b-diol-glucuronide reflect the peripheral tissue conversion of adrenal and gonadal precursor C19 steroids to active androgens [5]. A recent study suggests...

show abstract

“…Recently a number of investigators have studied the metabolism of testosterone by human skin taken from normal subjects and patients with testicular feminization. Gomez and Hsia (5) studied the metabolism of testosterone-"4C by skin slices obtained from normal subjects. They identified androstenedione, dihydrotestosterone, androstanedione, androsterone, and epiandrosterone as metabolites of testosterone.…”

Section: Introductionmentioning

confidence: 99%

Metabolism of testosterone-14C by cultured human cells

Shanie¹,

Hirschhorn²,

New³

1972

J. Clin. Invest.

View full text Add to dashboard Cite

A B S T R A C T The metabolism of "C-labeled testosterone by cultured human fibroblasts and amniotic fluid cells was investigated. Radiolabeled testosterone was incubated with the cultured cells for 48 hr, and the labeled metabolites present in the medium were subsequently identified. The major metabolic products of testosterone formed by cultured fibroblasts were A'-androstenedione, dihydrotestosterone, androsterone, and androstanediol. The amount of testosterone metabolized through each of two pathways was calculated and used to form a ratio designated the 17f-hydroxyl/17-ketonic ratio. Fibroblasts from normal male and female children and adult females had high 17P-hydroxyl/17-ketonic ratios indicating testosterone metabolism occurred primarily through the 17P-hydroxyl pathway. There was a change in the pattern of testosterone metabolism with age in males, i.e., adult males had much lower 17#-hydroxyl/17-ketonic ratios than did male children.The testosterone metabolism of fibroblast cultures derived from three children with testicular feminization and their mothers was compared to normal age and sexmatched controls. Fibroblasts of children with testicular feminization metabolized testosterone predominantly through the 17-ketonic pathway and manifested a pattern of testosterone metabolism distinctly different from their sex and age matched controls. The mothers of children with testicular feminization could be distinguished from normal females by their much lower 17#-hydroxyl/17-ketonic ratios. The much lower amounts of dihydrotestosterone and androstanediol produced by fibroblasts from patients with testicular feminization as

show abstract

In vitro metabolism of testosterone-4-¹⁴C and Δ⁴-androstene-3,17-dione-4¹⁴C in human skin

Cited by 145 publications

References 14 publications

Studies on testosterone metabolism in subjects with testicular feminization syndrome

Studies on testosterone metabolism in subjects with testicular feminization syndrome

Molecular cloning, expression and characterization of a monkey steroid UDP‐glucuronosyltransferase, UGT2B19, that conjugates testosterone

Metabolism of testosterone-14C by cultured human cells

Contact Info

Product

Resources

About