Browsing by Subject "Drug metabolism"

Now showing 1 - 5 of 5
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    Alcohol and medication interactions
    (U.S. National Institute on Alcohol Abuse and Alcoholism, 1999) Weathermon, Ron; Crabb, David W.; Medicine, School of Medicine
    Many medications can interact with alcohol, thereby altering the metabolism or effects of alcohol and/or the medication. Some of these interactions can occur even at moderate drinking levels and result in adverse health effects for the drinker. Two types of alcohol-medication interactions exist: (1) pharmacokinetic interactions, in which alcohol interferes with the metabolism of the medication, and (2) pharmacodynamic interactions, in which alcohol enhances the effects of the medication, particularly in the central nervous system (e.g., sedation). Pharmacokinetic interactions generally occur in the liver, where both alcohol and many medications are metabolized, frequently by the same enzymes. Numerous classes of prescription medications can interact with alcohol, including antibiotics, antidepressants, antihistamines, barbiturates, benzodiazepines, histamine H2 receptor antagonists, muscle relaxants, nonnarcotic pain medications and anti-inflammatory agents, opioids, and warfarin. In addition, many over-the-counter and herbal medications can cause negative effects when taken with alcohol.
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    Genome-Wide Discovery of Drug-Dependent Human Liver Regulatory Elements
    (PLOS (Public Library of Science), 2014-10-02) Smith, Robin P.; Eckalbar, Walter L.; Morrissey, Kari M.; Luizon, Marcelo R.; Hoffmann, Thomas J.; Sun, Xuefeng; Jones, Stacy L.; Aldred, Shelley Force; Ramamoorthy, Anuradha; Desta, Zeruesenay; Liu, Yunlong; Skaar, Todd C.; Trinklein, Nathan D.; Giacomini, Kathleen M.; Ahituv, Nadav; Department of Medicine, School of Medicine
    Inter-individual variation in gene regulatory elements is hypothesized to play a causative role in adverse drug reactions and reduced drug activity. However, relatively little is known about the location and function of drug-dependent elements. To uncover drug-associated elements in a genome-wide manner, we performed RNA-seq and ChIP-seq using antibodies against the pregnane X receptor (PXR) and three active regulatory marks (p300, H3K4me1, H3K27ac) on primary human hepatocytes treated with rifampin or vehicle control. Rifampin and PXR were chosen since they are part of the CYP3A4 pathway, which is known to account for the metabolism of more than 50% of all prescribed drugs. We selected 227 proximal promoters for genes with rifampin-dependent expression or nearby PXR/p300 occupancy sites and assayed their ability to induce luciferase in rifampin-treated HepG2 cells, finding only 10 (4.4%) that exhibited drug-dependent activity. As this result suggested a role for distal enhancer modules, we searched more broadly to identify 1,297 genomic regions bearing a conditional PXR occupancy as well as all three active regulatory marks. These regions are enriched near genes that function in the metabolism of xenobiotics, specifically members of the cytochrome P450 family. We performed enhancer assays in rifampin-treated HepG2 cells for 42 of these sequences as well as 7 sequences that overlap linkage-disequilibrium blocks defined by lead SNPs from pharmacogenomic GWAS studies, revealing 15/42 and 4/7 to be functional enhancers, respectively. A common African haplotype in one of these enhancers in the GSTA locus was found to exhibit potential rifampin hypersensitivity. Combined, our results further suggest that enhancers are the predominant targets of rifampin-induced PXR activation, provide a genome-wide catalog of PXR targets and serve as a model for the identification of drug-responsive regulatory elements.
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    Identification of rifampin-regulated functional modules and related microRNAs in human hepatocytes based on the protein interaction network
    (BioMed Central, 2016-08-22) Li, Jin; Wang, Ying; Dai, Xuefeng; Cong, Wang; Feng, Weixing; Xu, Chengzhen; Deng, Yulin; Wang, Yue; Skaar, Todd C.; Liang, Hong; Liu, Yunlong; Wang, Lei; Department of Medical and Molecular Genetics, IU School of Medicine
    BACKGROUND: In combination with gene expression profiles, the protein interaction network (PIN) constructs a dynamic network that includes multiple functional modules. Previous studies have demonstrated that rifampin can influence drug metabolism by regulating drug-metabolizing enzymes, transporters, and microRNAs (miRNAs). Rifampin induces gene expression, at least in part, by activating the pregnane X receptor (PXR), which induces gene expression; however, the impact of rifampin on global gene regulation has not been examined under the molecular network frameworks. METHODS: In this study, we extracted rifampin-induced significant differentially expressed genes (SDG) based on the gene expression profile. By integrating the SDG and human protein interaction network (HPIN), we constructed the rifampin-regulated protein interaction network (RrPIN). Based on gene expression measurements, we extracted a subnetwork that showed enriched changes in molecular activity. Using the Kyoto Encyclopedia of Genes and Genomes (KEGG), we identified the crucial rifampin-regulated biological pathways and associated genes. In addition, genes targeted by miRNAs that were significantly differentially expressed in the miRNA expression profile were extracted based on the miRNA-gene prediction tools. The miRNA-regulated PIN was further constructed using associated genes and miRNAs. For each miRNA, we further evaluated the potential impact by the gene interaction network using pathway analysis. RESULTS AND DISCCUSSION: We extracted the functional modules, which included 84 genes and 89 interactions, from the RrPIN, and identified 19 key rifampin-response genes that are associated with seven function pathways that include drug response and metabolism, and cancer pathways; many of the pathways were supported by previous studies. In addition, we identified that a set of 6 genes (CAV1, CREBBP, SMAD3, TRAF2, KBKG, and THBS1) functioning as gene hubs in the subnetworks that are regulated by rifampin. It is also suggested that 12 differentially expressed miRNAs were associated with 6 biological pathways. CONCLUSIONS: Our results suggest that rifampin contributes to changes in the expression of genes by regulating key molecules in the protein interaction networks. This study offers valuable insights into rifampin-induced biological mechanisms at the level of miRNAs, genes and proteins.
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    Micro-RNA regulation of hepatic drug metabolism : age-related changes in micro-RNA expression and genetic variants in micro-RNA target sites
    (2017-08-31) Burgess, Kimberly Sherrelle; Skaar, Todd C.; Arrizabalaga, Gustavo; Cummins, Theodore; Desta, Zeruesenay; Nass, Richard; Zhang, Jian-Tian
    Developmental changes in the liver significantly impact drug disposition. Due to the emergence of microRNAs as important regulators of drug disposition, we hypothesize that age-dependent change in microRNA expression and genetic variants in microRNA target sites contribute to variability in drug disposition. In human liver tissues, expression of 533 microRNAs and over 14,000 genes were measured. In all, 114 microRNAs were upregulated and 72 downregulated from fetal to pediatric, and 2 and 3, respectively, from pediatric to adult. Among these microRNAs, 99 microRNA-mRNA interactions were predicted or have previously been validated to target drug disposition genes and over 1,000 significant negative correlations were observed between miRNA-mRNA pairs. We validated these interactions using various cell culture models. Genetic variants in the promoter and coding regions of drug disposition genes have also been shown to alter enzyme expression and/or activity. However, these variants do not account for all variability in enzyme activity. Emerging evidence has shown that variants in the 3’UTR may explain variable drug response by altering microRNA regulation. Five 3’UTR variants were associated with significantly altered CYP2B6 activity in healthy human volunteers. The rs70950385 (AG>CA) variant was associated with decreased CYP2B6 activity among normal metabolizers. In vitro luciferase assays confirmed that the CA allele altered miR 1275 targeting of CYP2B6 mRNA. Due to the large number of 3’UTR variants predicted to alter microRNA regulation, a high-throughput method, PASSPORT-seq, was developed to test over 100 3’UTR variants simultaneously in different cell lines. Thirty-eight variants resulted in FDR-significant altered expression between wild-type and variant sequences. Our data suggest a mechanism for the marked changes in hepatic gene expression between the fetal and pediatric developmental periods, support a role for these age dependent microRNAs in regulating drug disposition, and provide strong evidence that 3’UTR variants are also an important source of variability in drug disposition.
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    Mouse Pharmacokinetics and In Vitro Metabolism of SH-11037 and SH-11008, Synthetic Homoisoflavonoids for Retinal Neovascularization
    (MDPI, 2022-10-24) Kim, Eun-yeong; Lee, Bit; Kwon, Sangil; Corson, Timothy W.; Seo, Seung-Yong; Lee, Kiho; Biochemistry and Molecular Biology, School of Medicine
    Cremastranone is a member of the homoisoflavanone family with anti-angiogenic activity in the eyes. SH-11037, a potent and selective synthetic homoisoflavonoid derived from cremastranone, was studied here for pharmacokinetics and metabolism characterization with a special focus on esterase-mediated hydrolysis. SH-11037 was shown to be converted rapidly and nearly completely to SH-11008 following an intravenous dose in mice. SH-11008 showed a high systemic clearance well exceeding the hepatic blood flow in mice. Neither SH-11037 nor SH-11008 were detected in plasma following oral administration of SH-11037 and SH-11008 in mice. Carboxylesterase was shown to be responsible for the rapid and quantitative hydrolysis of SH-11037 to SH-11008 in mouse plasma; the hydrolytic bioconversion was much slower in dog and human plasma, with butyrylcholinesterase and paraoxonase 1 likely being responsible. In vitro metabolism studies with liver S9 fractions suggested that SH-11008 was likely to have a high hepatic metabolic clearance with a predicted hepatic extraction ratio close to 1 in both mouse and human. In conclusion, SH-11037 and SH-11008 both appear to possess pharmacokinetic profiles suboptimal as a systemic agent. SH-11008 is suggested to possess a low potential for systemic toxicity suitable as a topical ocular therapeutic agent.