Involvement of the Multidrug and Toxic Compound Extrusion Transporter in Testosterone Release from Cultured Pig Leydig Cells

Abstract

Testosterone is considered to be released from Leydig cells via passive diffusion because of its hydrophobicity; however, the exact mechanism underlying testosterone secretion and the transporter involved are both unknown. Multidrug and toxic compound extrusion (MATE) transporters are predominantly found in the kidneys and liver and are thought to function in the elimination of metabolic organic cations during the final step of excretion in the kidney. In contrast, mMATE2 has been shown to be predominantly expressed in testicular Leydig cells. Although the physiological function of mMATE2 in Leydig cells is unknown, we hypothesized that mMATE2 acts as a testosterone exporter and is responsible for the secretion of testosterone from Leydig cells. Therefore, in the present study, we investigated the involvement of the MATE transporter in testosterone secretion from pig Leydig cells. Immunohistochemical analysis with anti-pig MATE2 antiserum indicated that the MATE transporter is present in pig Leydig cells. Additionally, treatment with the MATE inhibitors cimetidine and pyrimethamine reduced the testosterone secretion from pig Leydig cells but increased the intracellular testosterone levels. Estradiol release and intracellular estradiol level induced by human chorionic gonadotropin (hCG) further increased with cimetidine treatment. These results indicated that testosterone produced by hCG treatment is secreted from Leydig cells via the MATE transporter; however, in the presence of cimetidine or pyrimethamine, this MATE transporter-mediated secretion was inhibited, resulting in increased intracellular testosterone levels and estradiol production in Leydig cells. Thus, the MATE transporter may be responsible for testosterone secretion from Leydig cells.

Involvement of Human Multidrug and Toxic Compound Extrusion (MATE) Transporters in Testosterone Transport

“…However, it has been suggested that mMATE2 expressed in mouse testicular Leydig cells is involved in active testosterone secretion. 6) Our previous report suggests that pig MATE2 is responsible for testosterone secretion from Leydig cells. 7) However, Class III MATE transporters have not been identified in humans to date, and it is unclear which MATE transporters are involved in the secretion of testosterone in humans.…”

“…Consistent with our findings, previous reports have suggested that hMATE1 is a H + -coupled organic cation exporter. 4,6) Our previous report revealed that testosterone secretion from pig Leydig cells was significantly suppressed by cimetidine and PYR. Gynecomastia is known to be a possible side effect of cimetidine.…”

“…Based on the testis-specific expression of mMATE2 and cisinhibition analysis of testosterone, it has been suggested that mMATE2 is involved in testosterone transport. 6) Our previous study suggested that porcine MATE2 (Class III) is involved in testosterone secretion from testicular Leydig cells. 7) However, in humans, Class III MATE transporters specifically expressed in the testes have not been discovered.…”

Sweet Taste Receptor T1R3 Expressed in Leydig Cells Is Closely Related to Homeostasis of the Steroid Hormone Metabolism Profile

“…Experiment Design 3 (hCG Group). According to a previous study, 25 50 and 100 IU hCG were used to treat Leydig cells for 8 h to evaluate the steroidogenic capacity of Leydig cells.…”