Endosulfan‐α Induces CYP2B6 and CYP3A4 by Activating the Pregnane X Receptor

Abstract

Endosulfan can cause dysregulation of testosterone homeostasis in rodents. Postulated mechanisms involve activation of the pregnane X receptor (PXR) and/or the constitutive androstane receptor (CAR) to induce cytochrome P450 (CYP) enzymes. CYP 3A11 induction was tested using wild type, PXR-null, and human PXR (hPXR)-transgenic mice, as evidenced by metabolism of the anesthetic tribromoethanol (TBE). A significant (p < 0.05) reduction in TBE-induced sleep times, relative to controls, was observed in both wild type and hPXR mice pretreated with endosulfan-α at 2.5 mg/Kg/day for seven days, but no sleep time change was observed for PXR-null mice. CYP promoter activation was tested using HepG2 cells transiently transfected with plasmids containing constructs of CYP 3A4-luciferase, CYP 2B6-luciferase, and either hPXR or mouse CAR (mCAR). Exposure to endosulfan-α (10 μM for 24 hours) caused an 11-fold and 16-fold induction of CYP3A4 and CYP2B6 promoter activities, respectively, over controls in the presence of hPXR, but only a 3-fold enhancement of CYP 2B6 promoter activity in the presence of mCAR. Exposure of primary human hepatocytes to endosulfan-α (50 μM for 48 hours) resulted in enhanced testosterone hydroxylation, relative to controls, and elevation of CYP 2B6 and CYP 3A4 protein levels. Taken together, these data suggest that endosulfan may enhance testosterone metabolism in humans via the hPXR pathway.