Testosterone-mediated regulation of renal GSTA1/2 expression in male mice.

Abstract

Importance: Glutathione S-transferases (GSTs) are detoxifying enzymes that protect cells from xenobiotics. In mouse kidneys, class α GST (GSTA) isoforms display sexually dimorphic expression, with males exhibiting lower levels.

Objective: This study investigates the effect of testosterone on renal GSTA isoform expression in male mice.

Methods: Renal expression of GSTA1/2, GSTA3, and GSTA4 was examined in orchiectomized mice with or without testosterone supplementation, as well as in intact mice treated with antiandrogens including bicalutamide and flutamide or exhibiting either high (HT) or low (LT) serum testosterone levels.

Results: Orchiectomy increased the expression of GSTA1/2, GSTA3, and GSTA4 at both the mRNA and protein levels, accompanied by elevated enzyme activity measured using cumene hydroperoxide (CHP), a GSTA-specific substrate. Testosterone supplementation reversed these effects. Treatment with antiandrogens upregulated renal GSTA isoform expression in male mice, suggesting that GSTA isoform regulation is mediated through androgen receptor signaling. In male mice, GSTA1/2 expression was significantly lower in the HT group than in the LT group, while GSTA3 and GSTA4 expression remained relatively unchanged. Consistently, renal GST activity toward CHP was also lower in HT mice.

Conclusions and relevance: These suggest that testosterone suppresses renal GSTA isoform expression in male mice, with GSTA1/2 being more sensitive to testosterone-mediated inhibition than GSTA3 or GSTA4.