Re: A Closer Look At: S.H.B.G. & Metabolic Clearance.
In vitro influence of plasma steroid-binding proteins on androgen metabolism in human leukocytes.
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Henri Déchaud, a, , Raymond Goujona, Francine Claustrata, Michel Boucherata and Michel Pugeatb, c
a Hospices Civils de Lyon: Laboratoire Central de Biochimie Hôpital de l'Antiquaille, Lyon, France
b Hospices Civils de Lyon: Laboratoire de la Clinique Endocrinologique, Hôpital de l'Antiquaille, Lyon, France
c INSERM U329, Hôpital Debrousse, Lyon, France
Received 12 June 1994; accepted 19 August 1994. Available online 5 April 2000.
Abstract
The purpose of this study was to investigate the influence of plasma steroid-binding proteins on androgen metabolism in intact leukocytes prepared from normal male and female blood samples. Leukocyte preparations were incubated for 24 h at 37°C with either labeled or unlabeled testosterone (T), 5?-dihydrotestosterone (5?-DHT), and androstenedione (A). After extraction, the formed labeled metabolites were first identified by high performance liquid chromatography, then, using unlabeled substrates, metabolite concentrations were measured by specific radioimmunoassays. The conversion ratios of substrate to metabolite were calculated for each preparation using either labeled or unlabeled substrates. In the absence of steroid-binding proteins, the mean conversion ratios of T to A, A to T, T to 5?-DHT, and 5?-DHT to 3?-androstanediol (3?-D) were, in males and females, respectively, 5.6% and 6.1% (n = 11), 5.6% and 5.6% (n = 5), 2.8% and 2.2% (n = 11), 43.1% and 40.0% (n = 5), these sex differences being non-significant. The presence of increasing amounts of plasma, purified albumin or sex hormone binding-globulin (SHBG) in the incubation media reduced metabolite formation dose-dependently. However, a 1000-fold greater concentration of albumin than of SHBG was necessary for 50% inhibition of androgen metabolism by leukocytes, showing SHBG to have the main protective effect. Moreover, in the presence of various concentrations of T or 5?-DHT, and of albumin or SHBG, metabolite formation was positively and highly significantly correlated with the concentration of protein-unbound (free) substrate measured by equilibrium dialysis (r = 0.964 for conversion of T to A and r = 0.998 for conversion of 5?-DHT to 3?-D) but weakly correlated with total substrate concentration (r = 0.375 for total T and r = 0.669 for total 5?-DHT). Additionally, leukocyte metabolism of 5?-DHT was significantly enhanced when free 5?-DHT levels increased in the presence of 17?-estradiol (which displaced 5?-DHT from the SHBG-binding sites). We conclude that the metabolism of androgens by human leukocytes is mainly regulated by SHBG level, in both men and women. Although the rate of androgen metabolism by leukocytes was not determined in this study, reduced serum SHBG levels with unchanged albumin levels or drugs capable of displacing androgens from serum SHBG can be expected to increase androgen metabolism in human leukocytes.