Regulation of cytochrome P450-3A (CYP3A) and pregnane X receptor (PXR): Implications to drug-drug interactions

The nuclear receptor, pregnane x receptor (PXR) is a key regulator of expression of genes involved in drug metabolism and transport. Among these genes, the cytochrome P450 (CYP450) enzyme superfamily is involved in the metabolism of more than 90% of clinically used drugs and xenobiotics. Among the CYP450 enzymes, CYP3A enzyme sub-family is the most abundantly expressed in the adult liver and intestine and is responsible for the metabolism of almost two-thirds of prescription drugs. One of the interesting features of the CYP3A enzymes is that their expression can be regulated by either enzyme inhibition or enzyme induction. The induction of CYP3A enzymes is largely due to transcriptional activation and involves the activation of PXR. Given the fact that ∼60% of clinically used drugs and herbal remedies are CYP3A substrates, induction of this enzyme could result in harmful clinical consequences due to potentially dangerous drug-drug or herb-drug interactions. It is therefore necessary to elucidate the mechanisms regulating the induction of these enzymes in response to several xenobiotics. The aim of this dissertation was to study the underlying mechanisms leading to induction of CYP3A in response to xenobiotics. The findings presented in this dissertation provide important molecular bases for clinically important drug-drug and herb-drug interactions. The xenobiotics used in this study include the clinically used lipid lowering drug, clofibrate (CFA), also known as peroxisome proliferators; pregnenolone 16α carbonitrile (PCN), a known potent CYP3A inducer; and the herbal remedy kava kava. Understanding the mechanisms of induction of the most abundantly expressed and clinically important CYP450 isozyme, CYP3A, is may help to avoid potentially harmful drug interactions.