Comparative effects of the aromatase inhibitor R76713 and of its enantiomers R83839 and R83842 on steroid biosynthesis in vitro and in vivo
| Autor: | Wouters Walter Boudewijn Leopo, Alfons H. M. Raeymaekers, Ann Dillen, Jacky Van Dun, Marc Gaston Venet, Jozef H L Van Gelder, Roland De Coster, Eddy Jean Edgard Freyne, Marcel August Constant Janssen, M. D. W. G. Krekels, Gerard Charles Sanz |
|---|---|
| Rok vydání: | 1990 |
| Předmět: |
Male
medicine.medical_specialty Gonadotropins Equine medicine.drug_class Endocrinology Diabetes and Metabolism medicine.medical_treatment Clinical Biochemistry In Vitro Techniques Pharmacology Steroid biosynthesis Biochemistry Gonadotropin-Releasing Hormone Endocrinology Adrenocorticotropic Hormone Adrenal Cortex Hormones In vivo Internal medicine Testis medicine Animals Testosterone Aromatase Molecular Biology Granulosa Cells Aromatase inhibitor Estradiol biology Aromatase Inhibitors Chemistry Ovary Stereoisomerism Cell Biology Triazoles Rats Steroid hormone Enzyme inhibitor Steroid Hydroxylases Vorozole biology.protein Molecular Medicine Female Steroids medicine.drug |
| Zdroj: | The Journal of Steroid Biochemistry and Molecular Biology. 37:1049-1054 |
| ISSN: | 0960-0760 |
| Popis: | R76713 (6-[4-chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole) is a selective, non-steroidal aromatase inhibitor containing an asymmetric carbon atom. In this paper, we compare the effects of R76713 (racemate) with its enantiomers R83839 (the levo-isomer) and R83842 (the dextro-isomer) on steroid biosynthesis in rat cells in vitro and in the rat in vivo . In rat granulosa cells, aromatase activity was inhibited by 50% at concentrations of 0.93 nM of R76713, 240 nM of R83839 and 0.44 nM of R83842, revealing a 545-fold difference in activity between both enantiomers. Up to 1 μM, none of the compounds had any effect on steroid production in primary cultures of rat testicular cells. Above this concentration all three compounds showed a similar slight inhibition of androgen synthesis with a concomitant increase in the precursor progestins, indicative for some effect on the 17-hydroxylase/17,20-lyase enzyme. In rat adrenal cells none of the compounds showed any effect on corticosterone synthesis. At concentrations above 1 μM there was an increase in the levels of 11-deoxycorticosterone pointing towards an inhibition of the 11-hydroxylase enzyme. This increase was more pronounced for R83839 than for R76713 and R83842. In vivo , in PMSG-primed rats, R83842 reduced plasma estradiol by 50%, 2 h after oral administration of 0.0034 mg/kg, whereas 0.011 mg/kg of R76713 and 0.25 mg/kg of R83839 were needed to obtain the same result. Oral administration of up to 20 mg/kg of the compounds did not significantly affect plasma levels of adrenal steroids in LHRH/ACTH-injected rats. Plasma testosterone was lowered at 10 and 20 mg/kg of R83842 and at the highest dose (20 mg/kg) of R76713 and R83839. In conclusion, the present study shows that the aromatase inhibitory activity of R76713 resides almost exclusively in its dextro-isomer R83842. R83842 exhibits a specificity for aromatase as compared to other enzymes involved in steroid biosynthesis of at least a 1000-fold in vitro as well as in vivo . This confirms the extreme selectivity previously found for the racemate. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|