Androgen Receptor is Responsible for Rat Organic Cation Transporter 2 Gene Regulation but not for rOCT1 and rOCT3

Asaka, Jun-ichi
Terada, Tomohiro
Okuda, Masahiro
Katsura, Toshiya
Inui, Ken-ichi

¹Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan.

^*Author for correspondence; E-mail: [email protected]

Received: 18 October 2005; Accepted: 7 December 2005.

Pharmaceutical Research 23(4):p 697-704, April 2006.

Purpose

Organic cation transporters 1–3 (OCT1–3; Slc22a1–3) mediate the membrane transport of organic cations in the kidney. We previously reported that rat (r)OCT2 expression in the kidney was regulated by testosterone. In this study, we examined the transcriptional mechanisms underlying the testosterone-dependent regulation of rOCT2 expression.

Methods

Approximately 3000-bp fragments of the rOCT1–3 promoter region were isolated, and promoter activities were measured in the renal epithelial cell line LLC-PK₁ with the coexpression of rat androgen receptor.

Results

Among reporter constructs tested, only rOCT2 promoter activity was stimulated by testosterone. This stimulation was suppressed by nilutamide, an antiandrogen drug. Reporter assays using deletion constructs and mutational constructs of putative androgen response elements (ARE) in the rOCT2 promoter region suggested that two AREs, located at approximately −3000 and −1300, respectively, play an important role in the induction by testosterone.

Conclusions

Testosterone induces the expression of rOCT2, but not of rOCT1 and rOCT3, via the AR-mediated transcriptional pathway. This is the first study to address the transcriptional mechanisms of testosterone-dependent gene regulation of the Slc22 family.