Testosterone and Estradiol Affect Renal Oxidative Metabolism and Glutathione Pathway of Wistar Rats

Abstract

IntroductionEffects of androgens on drug metabolism of the liver are well known and these are attributed to anabolic properties of the hormones [1,2]. On the other hand, the impact of the influence of the sexual hormones on kidney metabolism is relevant in the modulation of nephrotoxic substances effect. Early studies of Smith et al. [3] showed that androgens regulate cytochrome P450 (CYP) expression in renal mouse: infact CYP content of male mice was 3-4 folds higher than female one. Changes of androgen concentration modified enzyme content, confirming that expression of renal CYP gene is inducible or repressible by male hormones [4,5]. Further, level of CYPIIE1 is usually much higher in male than in female mice: testosterone treatment induced female CYPIIE1 content at level similar to that of male [6].Sexual differences were observed in phase II metabolism also: liver glutathione S-transferases (GST) showed that substrate is determinant for the enzyme activity. For instance, the enzyme had higher activity in male than in female rats with a variety of substrates [7,8], thus underlining significant gender-related differences [9]. On the contrary, renal GST activities were higher with several substrates in female than in male rats [10] and sex differences were found also in isophorms of rat and human enzyme [11]. In addition, the half-life of renal reduced glutathione (GSH) is shorter in male (29 minutes) than in female (57 minutes) mouse [12].Finally, mouse kidney shows a greater cysteine conjugate ß-lyase (ßL) activity in females than in males [13].Sexual dimorphism was also recently established for ornithine aminotransferase in the mouse kidney [14] that is naturally downregulated by testosterone, or renal organic anion transporter 2 in rat and mice kidney that exhibits gender differences such as strong androgen inhibition and weak estrogen and progesterone stimulation [15].The aim of the present research was to get further insights in the knowledge of the effects of testosterone, estradiol, and castration on renal oxidative metabolism (CYP), glutathione pathway (GSH content and GST activities), and cysteine-conjugate ß-lyase (GTK) activity in rats. AbstractThe impact of sexual hormones on kidney metabolism may be relevant to modulate the effect of nephrotoxic substances. In the present research the effects of castration, testosterone, and estradiol on renal oxidative metabolism [cytochrome P-450 (CYP)], glutathione pathway [glutathione content (GSH), glutathione S-transferases (GST) activities, and cysteine-conjugate ß-lyase [as glutamine transaminase K (GTK) activity] have been studied. Naive male rats have a significantly lower GSH content but show a significantly higher GST activities and CYP content than females, whereas no sex difference was for GTK activity. Castration significantly reduces GSH content and GTK activity in females and CYP content in males, partially but significantly restored by testosterone. Testosterone significantly increases GSH content and GTK activity in males and GTK activity and...