ABSTRACT
Pregnane X receptor (PXR) is the major regulator of xenobiotic metabolism. PXR itself is controlled by various signaling molecules including glucocorticoids. Moreover, negative feed-back regulation has been proposed at the transcriptional level. We examined the involvement of the 3'-untranslated region (3'-UTR) of mRNA and microRNAs in PXR- and glucocorticoid receptor (GR)-mediated regulation of gene expression. PXR ligands were found to significantly downregulate mRNA expression in a set of 14 human hepatocyte cultures. Similarly, PXR was downregulated by PCN in the C57/BL6 mice liver. In mechanistic studies with the full-length 3'-UTR cloned into luciferase reporter or expression vectors, we showed that the 3'-UTR reduces PXR expression. From the miRNAs tested, miR-18a-5p inhibited both expression and gene induction. Importantly, we observed significant upregulation of miR-18a-5p expression 6 h after treatment with the PXR ligand rifampicin, which indicates a putative mechanism underlying negative feed-back regulation in hepatic cells. Additionally, glucocorticoids upregulated expression not only through the promoter region but also 3'-UTR regulation, which likely involves downregulation of miR-18a-5p. We conclude that miR-18a-5p is involved in the down-regulation of expression by its ligands and in the upregulation of mRNA expression by glucocorticoids in hepatic cells.
ABSTRACT
Mounting evidence demonstrates that CYP2B6 plays a much larger role in human drug metabolism than was previously believed. The discovery of multiple important substrates of CYP2B6 as well as polymorphic differences has sparked increasing interest in the genetic and xenobiotic factors contributing to the expression and function of the enzyme. The expression of CYP2B6 is regulated primarily by the xenobiotic receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) in the liver. In addition to CYP2B6, these receptors also mediate the inductive expression of CYP3A4, and a number of important phase II enzymes and drug transporters. CYP2B6 has been demonstrated to play a role in the metabolism of 2%-10% of clinically used drugs including widely used antineoplastic agents cyclophosphamide and ifosfamide, anesthetics propofol and ketamine, synthetic opioids pethidine and methadone, and the antiretrovirals nevirapine and efavirenz, among others. Significant inter-individual variability in the expression and function of the human CYP2B6 gene exists and can result in altered clinical outcomes in patients receiving treatment with CYP2B6-substrate drugs. These variances arise from a number of sources including genetic polymorphism, and xenobiotic intervention. In this review, we will provide an overview of the key players in CYP2B6 expression and function and highlight recent advances made in assessing clinical ramifications of important CYP2B6-mediated drug-drug interactions.
ABSTRACT
Intestine is responsible for the biotransformation of many orally-exposed chemicals. The constitutive androstane receptor (CAR/Nr1i3) is known to up-regulate many genes encoding drug-metabolizing enzymes and transporters (drug-processing genes/DPGs) in liver, but less is known regarding its effect in intestine. Sixty-day-old wild-type andmice were administered the CAR-ligand TCPOBOP or vehicle once daily for 4 days. In wild-type mice,mRNA was down-regulated by TCPOBOP in liver and duodenum.mice had altered basal intestinal expression of many DPGs in a section-specific manner. Consistent with the liver data (Aleksunes and Klaassen, 2012), TCPOBOP up-regulated many DPGs (, and) in specific sections of small intestine in a CAR-dependent manner. However, the mRNAs ofandwere previously known to be up-regulated by TCPOBOP in liver but were not altered in intestine. Interestingly, many known CAR-target genes were highest expressed in colon where CAR is minimally expressed, suggesting that additional regulators are involved in regulating their expression. In conclusion, CAR regulates the basal expression of many DPGs in intestine, and although many hepatic CAR-targeted DPGs wereCAR-targets in intestine, pharmacological activation of CAR in liver and intestine are not identical.
ABSTRACT
The drug metabolism is a biochemical process on modification of pharmaceutical substances through specialized enzymatic systems. Changes in the expression of drug-metabolizing enzyme genes can affect drug metabolism. Recently, epigenetic regulation of drug-metabolizing enzyme genes has emerged as an important mechanism. Epigenetic regulation refers to heritable factors of genomic modifications that do not involve changes in DNA sequence. Examples of such modifications include DNA methylation, histone modifications, and non-coding RNAs. This review examines the widespread effect of epigenetic regulations on genes involved in drug metabolism, and also suggests a network perspective of epigenetic regulation. The epigenetic mechanisms have important clinical implications and may provide insights into effective drug development and improve safety of drug therapy.
ABSTRACT
Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia. Here, these associations are reviewed with respect to liver metabolism and disease.