Impact of obese levels on the hepatic expression of nuclear receptors and drug-metabolizing enzymes in adult and offspring mice.
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ABSTRACT:
SUBMITTER: Wang P
PROVIDER: S-EPMC6976990 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Interindividual variability in the expression of drug-metabolizing enzymes and transporters (DMETs) in human liver may contribute to interindividual differences in drug efficacy and adverse reactions. Published studies that analyzed variability in the expression of DMET genes were limited by sample sizes and the number of genes profiled. We systematically analyzed the expression of 374 DMETs from a microarray data set consisting of gene expression profiles derived from 427 human liver samples. The standard deviation of interindividual expression for DMET genes was much higher than that for non-DMET genes. The 20 DMET genes with the largest variability in the expression provided examples of the interindividual variation. Gene expression data were also analyzed using network analysis methods, which delineates the similarities of biological functionalities and regulation mechanisms for these highly variable DMET genes. Expression variability of human hepatic DMET genes may affect drug-gene interactions and disease susceptibility, with concomitant clinical implications.
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Project description:BackgroundWilson's disease is a genetic disorder inherited in a recessive manner, caused by mutations in the copper-transporter ATP7B. Although it is a well-known disease, currently available treatments are far from satisfactory and their efficacy varies in individual patients. Due to the lack of information about drug-metabolizing enzymes and drug transporters profile in Wilson's disease livers, we aimed to evaluate the mRNA expression and protein abundance of selected enzymes and drug transporters in this liver disorder.MethodsWe analyzed gene expression (qPCR) and protein abundance (LC-MS/MS) of 14 drug-metabolizing enzymes and 16 drug transporters in hepatic tissue from Wilson's disease patients with liver failure (n = 7, Child-Pugh class B and C) and metastatic control livers (n = 20).ResultsIn presented work, we demonstrated a downregulation of majority of CYP450 and UGT enzymes. Gene expression of analyzed enzymes ranged between 18 and 65% compared to control group and significantly lower protein content of CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP3A4 and CYP3A5 enzymes was observed in Wilson's disease. Moreover, a general decrease in hepatocellular uptake carriers from SLC superfamily (significant at protein level for NTCP and OATP2B1) was observed. As for ABC transporters, the protein abundance of BSEP and MRP2 was significantly lower, while levels of P-gp and MRP4 transporters were significantly higher in Wilson's disease.ConclusionsAltered hepatic expression of drug-metabolizing enzymes and drug transporters in Wilson's disease patients with liver failure may result in changes of drug pharmacokinetics in that group of patients.
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Project description:The transcriptional regulation of drug-metabolizing enzymes and transporters (here collectively referred to as DMEs) in the developing proximal tubule (PT) is not well understood. As in the liver, DME regulation in the PT may be mediated through nuclear receptors, which are thought to "sense" deviations from homeostasis by being activated by ligands, some of which are handled by DMEs, including drug transporters. Systems analysis of transcriptomic data during kidney development predicted a set of upstream transcription factors, including hepatocyte nuclear factor 4α (Hnf4a) and Hnf1a, as well as Nr3c1 (Gr), Nfe2l2 (Nrf2), peroxisome proliferator-activated receptor α (Pparα), and Tp53. Motif analysis of cis-regulatory enhancers further suggested that Hnf4a and Hnf1a are the main transcriptional regulators of DMEs in the PT. Available expression data from tissue-specific Hnf4a knockout tissues revealed that distinct subsets of DMEs were regulated by Hnf4a in a tissue-specific manner. Chromatin immunoprecipitation combined with massively parallel DNA sequencing was performed to characterize the PT-specific binding sites of Hnf4a in rat kidneys at three developmental stages (prenatal, immature, adult), which further supported a major role for Hnf4a in regulating PT gene expression, including DMEs. In ex vivo kidney organ culture, an antagonist of Hnf4a (but not a similar inactive compound) led to predicted changes in DME expression, including among others Fmo1, Cyp2d2, Cyp2d4, Nqo2, as well as organic cation transporters and organic anion transporters Slc22a1 (Oct1), Slc22a2 (Oct2), Slc22a6 (Oat1), Slc22a8 (Oat3), and Slc47a1 (Mate1). Conversely, overexpression of Hnf1a and Hnf4a in primary mouse embryonic fibroblasts, sometimes considered a surrogate for mesenchymal stem cells, induced expression of several of these proximal tubule DMEs, as well as epithelial markers and a PT-enriched brush border marker Ggt1. These cells had organic anion transporter function. Taken together, the data strongly supports a critical role for HNF4a and Hnf1a in the tissue-specific regulation of drug handling and differentiation toward a PT-like cellular identity. We discuss our data in the context of the "remote sensing and signaling hypothesis" (Ahn and Nigam, 2009; Wu et al., 2011).
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