Meclizine is an agonist of human pregnane X receptor

Abstract

Pregnane X receptor (PXR) is a receptor that regulates the transcription of genes involved in various functions, including drug metabolism and transport. Conflicting data exist as to whether meclizine, which is a histamine H1 antagonist, is an activator of human PXR (hPXR). Therefore, we conducted a detailed, systematic investigation to assess the effect of meclizine on hPXR activity by performing a cell‐based reporter gene assay, a time‐resolved fluorescence resonance energy transfer competitive ligand‐binding assay, a mammalian two‐hybrid assay to assess coactivator recruitment, and a hPXR target gene expression assay. Given the pronounced species differences in PXR activation, we also compared the effect of meclizine on rat PXR (rPXR) and hPXR function. In transfected HepG2 cells, meclizine activated hPXR to a greater extent than rPXR. The drug bound to hPXR ligand‐binding domain and recruited steroid receptor coactivator‐1 to the receptor. Consistent with its hPXR agonism, meclizine increased hPXR target gene (CYP3A4) mRNA expression in cultured human hepatocytes. However, it did not increase but decreased testosterone 6β‐hydroxylation, suggesting inhibition of CYP3A catalytic activity. In conclusion, our principal findings indicate species differences in hPXR and rPXR activation by meclizine and its mechanism of hPXR activation involves receptor agonism.[Supported by CIHR and MSFHR]

New in Vitro Tools to Study Human Constitutive Androstane Receptor (CAR) Biology: Discovery and Comparison of Human CAR Inverse Agonists

“…These findings support the very recent report that meclizine could not repress constitutive or CITCO-enhanced human CAR reporter activity and CYP2B6 expression in primary hepatocytes. 53 Together, these two studies strongly suggest that meclizine is not an inverse agonist for human CAR. In contrast, we identified an unrelated chemical S07662 that is, at equimolar concentrations, more efficacious than the previously reported inverse agonists.…”