Liver X receptor α bidirectionally transactivates human CYP1A1 and CYP1A2 through two cis-elements common to both genes

Abstract

CYP1A1 and CYP1A2 are involved in both detoxification and metabolic activation of xenobiotics. Human CYP1A1 (hCYP1A1) and hCYP1A2 exist in a head-to-head orientation in chromosome 15 with the overlapping 5′-flanking region. We have recently reported that nuclear receptor constitutive androstane receptor (CAR), in addition to aryl hydrocarbon receptor, bidirectionally transactivates these genes through common motifs. In this study, we have investigated a role of liver X receptor α (LXRα), another liver-enriched nuclear receptor, in the expression hCYP1A1 and hCYP1A2. In reporter assays with dual-reporter constructs containing their promoter region between two different reporter genes, LXRα simultaneously transactivated hCYP1A1 and hCYP1A2 through two regions, independent of aryl hydrocarbon receptor. In electrophoretic mobility shift assays, LXRα/retinoid X receptor α heterodimer bound to two ER8-type motifs found at around −520 and −460 of hCYP1A1. The former corresponds to the CAR-binding motif previously identified. Reporter assays using mutated constructs confirmed the critical roles of these motifs in the LXRα-mediated simultaneous transcription of hCYP1A1 and hCYP1A2. hCYP1A1 and hCYP1A2 mRNA levels were increased in human hepatoma HuH-7 cells and human primary hepatocytes, respectively, after treatment with the LXRα ligand GW3965. Our results suggest that LXRα transactivates the expression of hCYP1A1 and hCYP1A2 through common two cis-elements.