Triphenyltin and Tributyltin inhibit pig testicular 17β-hydroxysteroid dehydrogenase activity and suppress testicular testosterone biosynthesis

Abstract

We previously reported that tributyltin chloride (TBT) and triphenyltin chloride (TPT) powerfully suppressed human chorionic gonadotropin- and 8-bromo-cAMP-stimulated testosterone production in pig Leydig cells at concentrations that were not cytotoxic [Nakajima Y, Sato Q, Ohno S, Nakajin S. Organotin compounds suppress testosterone production in Leydig cells from neonatal pig testes. J Health Sci 2003;49:514–9]. This study investigated the effects of these organotin compounds on the activity of enzymes involved in testosterone biosynthesis in pig testis. At relatively low concentrations of TPT, 17β-hydroxysteroid dehydrogenase (17β-HSD; IC 50 = 2.6 μM) and cytochrome P450 17α-hydroxylase/C 17–20 lyase (IC 50 = 117 μM) activities were inhibited, whereas cholesterol side-chain cleavage cytochrome P450 and 3β-HSD/Δ 4–Δ 5 isomerase activities were less sensitive. Overall, TPT was more effective than TBT. TPT also inhibited both ferredoxin reductase and P450 reductase activities at concentrations over 30 μM; however, TBT had no effect, even at 100 μM. The IC 50 values of TPT were estimated to be 25.7 and 22.8 μM for ferredoxin reductase and P450 reductase, respectively. The inhibitory effect of TPT (30 μM) on microsomal 17β-HSD activity from pig testis was eliminated by pretreatment with the reducing agents dithiothreitol (1 mM) and dithioerythritol (1 mM). On the other hand, TPT (0.03 μM) or TBT (0.1 μM) exposure suppressed the testosterone production from androstenedione in pig Leydig cells indicating that these organotins inhibit 17β-HSD activity in vivo as well as in vitro, and the IC 50 values of TPT and TBT for 17β-HSD activity were estimated to be 48 and 114 nM, respectively. Based on these results, it appears possible that the effects of TBT and TPT are largely due to direct inhibition of 17β-HSD activity in vivo.