Hepatic GSTP1/2 Exhibits High Sensitivity to Testosterone-Mediated Regulation in Mice

Glutathione S-transferases (GSTs) are essential phase II detoxification enzymes encoded by a diverse gene superfamily. Among them, the pi class (GSTP) includes 2 isozymes, GSTP1 and GSTP2, which share a high degree of sequence similarity. In mice, hepatic GSTP1/2 expression is higher in males than in females. To investigate the regulatory mechanisms underlying this sex difference, we examined orchiectomized mice treated with testosterone. Orchiectomy reduced hepatic GSTP1/2 expression and associated enzyme activity, both of which were restored following testosterone administration. To assess the sensitivity of GSTP1/2 to testosterone fluctuations, we compared mice experiencing a serum testosterone surge with those maintaining baseline levels. Mice with elevated testosterone exhibited increased hepatic GSTP1/2 protein expression and enzyme activity, demonstrating the high responsiveness of GSTP1/2 to testosterone. To our knowledge, this is the first study to demonstrate that testosterone surges regulate both the expression and enzymatic function of a specific protein. These findings underscore testosterone's critical role in the male-dominant expression of GSTP1/2 and highlight its sensitivity to physiological fluctuations in testosterone levels. Further studies are warranted to elucidate the molecular mechanisms by which testosterone surges influence gene expression.