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Les endozépines, facteurs locaux de régulation de la stéroïdogenèse testiculaire

Endozepines: local testicular steroidogenesis regulation factors

Andrologie volume 13, pages 273–287 (2003)Cite this article

Resume

Les fonctions testiculaires endocrines et exocrines sont soumises à un contrôle multifactoriel complexe, impliquant les gonadotrophines circulantes et des signaux produitsin situ responsables de régulations locales. Parmi ces facteurs locaux, les endozépines (EZ), ligands endogènes des récepteurs des benzodiazépines (BZD), semblent exercer un effet stimulant de type intracrine, autocrine et/ou paracrine sur la sécrétion leydigienne. Les effets des BZD sont relayés par deux types de récepteurs, le récepteur des BZD de type central (CBR) associé au complexe-récepteur GABAA-canal chlore, et le récepteur de type périphérique (PBR) principalement localisé sur la membrane mitochondriale et très abondant dans les cellules stéroïdogènes. La recherche de ligands endogènes pour ces récepteurs a permis l’identification d’une nouvelle famille de peptides, les EZ.

Toutes les EZ identifiées à ce jour dérivent d’un même précurseur, lediazepam-binding inhibitor (DBI) dont le clivage protéolytique conduit à différents peptides biologiquement actifs tels que le triakontatétraneuropeptide DBI17–50 (TTN) ou l’octadécaneuropeptide DBI33–50 (ODN). Les EZ sont très largement distribuées dans le cerveau et dans la plupart des organes périphériques en particulier les glandes stéroïdogènes,i.e. surrénale, testicule...

Différents travaux réalisés chez le rat suggèrent l’existence d’une implication des EZ dans le contrôle de la stéroïdogenèse testiculaire. Ainsi, l’expression du gène du DBI et la présence de peptides apparentés au DBI dans les cellules de Sertoli, de Leydig et dans certaines cellules germinales ont été démontrées. En outre, les EZ sont capables de stimuler la libération de progestérone et de testostérone par des cellules de Leydig de rat en culture et par des cellules de Leydig des lignées tumorales MA-10 ou R2C. Enfin, des études pharmacologiques ont montré que les effets des EZ sur la stéroïdogenèse testiculaire du rat s’exercentvia l’activation d’un PBR. Le PBR serait alors le dernier maillon d’une chaîne d’interactions protéiques permettant la transduction des signaux de stimulation de la stéroïdogenèse, aboutissant à la translocation du cholestérol vers la membrane mitochondriale interne, où il est converti en prégnénolone, grâce à l’action enzymatique du cytochrome P450scc.

Abstract

Testicular endocrine and exocrine functions are controlled by multiple signals including circulating gonadotropins and locally produced factors. Among these factors, endozepines (EZ), which are the endogenous ligands for benzodiazepine receptors, seem to exert an intracrine, autocrine and/or paracrine stimulatory effect on Leydig cell testosterone production. Benzodiazepine effects are mediated by two types of receptors, i.e. the central-type benzodiazepine receptor (CBR) associated with the GABAA-receptor complex, and the peripheral-type benzodiazepine receptor (PBR) principally located on the mitochondrial membrane and extremely abundant in steroidogenic cells. All EZ characterized to date are derived from an 86 amino acid polypeptide called diazepam binding inhibitor (DBI) that generates, via proteolytic cleavage, several biologically active peptides including the triakontatetraneuropeptide DBI17-50 (TTN) and the octadecaneuropeptide DBI33-50 (ODN). EZ are widely distributed in the brain and various peripheral organs, particularly in steroidogenic glands. A number of data suggest that, in rats, EZ could regulate testicular steroidogenesis. Firstly, DBI gene expression and the presence of DBI-like peptides have been shown in Sertoli cells, Leydig cells and in late-differentiated germ cells. Moreover, EZ are able to stimulate progesterone and testosterone production by rat Leydig cells and by MA-10 or R2C Leydig tumor cells. Finally, pharmacological studies have shown that EZ stimulate rat testicular steroidogenesis via activation of PBR. PBR appears to be an important component of a dynamic multistep process involving protein-protein interactions, to promote cholesterol translocation in the mitochondria, where it is converted into pregnenolone by cytochrome P450scc.

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  1. IFRMP23, Laboratoire de Neuroendocrinologie Cellulaire et Moléculaire, INSERM U-413, Université de Rouen, Mont Saint Aignan

    Céline Duparc, Hervé Lefebvre, Marie -Christine Tonon, Hubert Vaudry & Jean Marc Kuhn

  2. Service d’Endocrinologie et Maladies Métaboliques, INSERM U-413, IFRMP 23, CHU de Rouen, Hôpital de Bois Guillaume, 1 rue de Germont, 76031, Rouen Cedex, France

    Hervé Lefebvre & Jean Marc Kuhn

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Duparc, C., Lefebvre, H., Tonon, M.C. et al. Les endozépines, facteurs locaux de régulation de la stéroïdogenèse testiculaire. Androl. 13, 273–287 (2003). https://doi.org/10.1007/BF03034882

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