Biological relevance of PPM1B phosphatase regulation of PXR‐mediated CYP3A expression in hepatocytes (1141.9)

Abstract

Variations in pregnane xenobiotic receptor (PXR)‐mediated cytochrome P450 3A (CYP3A) expression can alter therapeutic response to a variety of drugs. It was previously shown that Mg2+/Mn2+‐dependent phosphatase 1B (PPM1B) levels positively regulate human PXR (hPXR) transactivating function and negatively regulate proliferation of HepG2 cells. In the current study, we sought to determine the biological relevance of this regulation. In COS‐7 cells, PPM1B increased hPXR transactivation of CYP3A4 promoter activity and coimmunoprecipitated with hPXR. Elevated PPM1B levels in HepG2 cells led to a significant attenuation of hPXR inhibition by TNFα. This finding, together with the previous finding of PPM1B attenuation of hPXR inhibition by CDK2, suggests that PPM1B counteracts PXR inhibition by proliferation‐dependent signaling pathways in hepatocytes. In mice regenerating livers, gene expression of PPM1B and Cyp3a11 (ortholog of human CYP3A4) was found to be downregulated, although PXR levels were marginally upregulated. Similarly, PPM1B and CYP3A4 gene levels were downregulated in human hepatocellular carcinoma livers with no significant change in hPXR gene levels. Together, these results show that PPM1B interacts with PXR, and increases PXR function by counteracting proliferation‐dependent PXR inhibitory signaling pathways in hepatocytes. Furthermore, downregulation of PPM1B levels in regenerating and hepatocellular carcinoma livers may in part explain a mechanism for repression of PXR‐mediated CYP3A levels in these liver pathophysiologies.Grant Funding Source: Supported by Auburn University Animal Health and Disease Research grant and Start Up funds