Transcriptional regulation of CYP3A4 by nuclear receptors in human hepatocytes under hypoxia.

The human hepatic cytochrome P-450 3A4 (CYP3A4), recognized as a multifunctional enzyme, has a wide range of substrates including commonly used drugs. Previous investigations demonstrated that the expression of CYP3A4 in human hepatocytes could be regulated by some nuclear receptors (NRs) at transcriptional level under diverse situations. The significance of oxygen on CYP3A4-mediated metabolism seems notable while the regulatory mode of CYP3A4 in the particular case still remains elusive. Recently, striking evidence has emerged that both CYP3A4 and its regulator NR could be inhibited by exposure to hypoxia. Therefore, it is of great importance to elucidate whether and how these NRs act in the transcriptional regulation of CYP3A4 in human hepatocytes under hypoxic conditions. In this review, we mainly summarized transcriptional regulation of the pivotal enzyme CYP3A4 by NRs and explored the possible regulatory pathways of CYP3A4 via these major NRs under hypoxia, expecting to provide favorable evidence for further clinical guidance under such pathological situations.