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12 Publications visible to you, out of a total of 12
Hepatic Expression of the Na+-Taurocholate Cotransporting Polypeptide Is Independent from Genetic Variation

Abstract (Expand)

The hepatic Na+-taurocholate cotransporting polypeptide NTCP/SLC10A1 is important for the uptake of bile salts and selected drugs. Its inhibition results in increased systemic bile salt concentrations. …oncentrations. NTCP is also the entry receptor for the hepatitis B/D virus. We investigated interindividual hepatic SLC10A1/NTCP expression using various omics technologies. SLC10A1/NTCP mRNA expression/protein abundance was quantified in well-characterized 143 human livers by real-time PCR and LC-MS/MS-based targeted proteomics. Genome-wide SNP arrays and SLC10A1 next-generation sequencing were used for genomic analyses. SLC10A1 DNA methylation was assessed through MALDI-TOF MS. Transcriptomics and untargeted metabolomics (UHPLC-Q-TOF-MS) were correlated to identify NTCP-related metabolic pathways. SLC10A1 mRNA and NTCP protein levels varied 44-fold and 10.4-fold, respectively. Non-genetic factors (e.g., smoking, alcohol consumption) influenced significantly NTCP expression. Genetic variants in SLC10A1 or other genes do not explain expression variability which was validated in livers (n = 50) from The Cancer Genome Atlas. The identified two missense SLC10A1 variants did not impair transport function in transfectants. Specific CpG sites in SLC10A1 as well as single metabolic alterations and pathways (e.g., peroxisomal and bile acid synthesis) were significantly associated with expression. Inter-individual variability of NTCP expression is multifactorial with the contribution of clinical factors, DNA methylation, transcriptional regulation as well as hepatic metabolism, but not genetic variation.

Authors: Roman Tremmel, Anne T. Nies, Barbara A. C. van Eijck, Niklas Handin, Mathias Haag, Stefan Winter, Florian A. Büttner, Charlotte Kölz, Franziska Klein, Pascale Mazzola, Ute Hofmann, Kathrin Klein, Per Hoffmann, Markus M. Nöthen, Fabienne Z. Gaugaz, Per Artursson, Matthias Schwab, Elke Schaeffeler

Date Published: 1st Jul 2022

Publication Type: Journal

The fruit fly Drosophila melanogaster as an innovative preclinical ADME model for solute carrier membrane transporters, with consequences for pharmacology and drug therapy.

Abstract (Expand)

Solute carrier membrane transporters (SLCs) control cell exposure to small-molecule drugs, thereby contributing to drug efficacy and failure and/or adverse effects. Moreover, SLCs are genetically linked … to various diseases. Hence, in-depth knowledge of SLC function is fundamental for a better understanding of disease pathophysiology and the drug development process. Given that the model organism Drosophila melanogaster (fruit fly) expresses SLCs, such as for the excretion of endogenous and toxic compounds by the hindgut and Malpighian tubules, equivalent to human intestine and kidney, this system appears to be a promising preclinical model to use to study human SLCs. Here, we systematically compare current knowledge of SLCs in Drosophila and humans and describe the Drosophila model as an innovative tool for drug development.

Authors: Y. Wang, B. Moussian, E. Schaeffeler, M. Schwab, A. T. Nies

Date Published: 12th Jun 2018

Publication Type: Not specified

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy.

Abstract (Expand)

The solute carrier (SLC) SLC16 gene family comprises 14 members and encodes for monocarboxylate transporters (MCTs), which mediate the absorption and distribution of monocarboxylic compounds across … plasma membranes. As the knowledge about their physiological function, activity, and regulation increases, their involvement and contribution to cancer and other diseases become increasingly evident. Moreover, promising opportunities for therapeutic interventions by directly targeting their endogenous functions or by exploiting their ability to deliver drugs to specific organ sites emerge.

Authors: P. Fisel, E. Schaeffeler, M. Schwab

Date Published: 17th Apr 2018

Publication Type: Not specified

Systemic regulation of bilirubin homeostasis: Potential benefits of hyperbilirubinemia

Abstract (Expand)

Neurotoxic bilirubin is the end product of heme catabolism in mammals. Bilirubin is solely conjugated by uridine diphospho-glucuronosyltransferase 1A1, which is a membrane-bound enzyme that catalyzes … the transfer of glucuronic acid. Due to low function of hepatic and intestinal uridine diphospho-glucuronosyltransferase 1A1 during the neonatal period, human neonates develop mild to severe physiological hyperbilirubinemia. Accumulation of bilirubin in the brain leads to the onset of irreversible brain damage, termed kernicterus. Breastfeeding is one of the most significant factors that increase the risk of developing kernicterus in infants. Why does this most natural way of feeding increase the risk of brain damage or even death? This question leads to the hypothesis that breast milk-induced hyperbilirubinemia might bring certain benefits that outweigh those risks. While bilirubin is neurotoxic and cytotoxic, this compound is also a potent antioxidant. There are studies showing improved clinical conditions in patients with hyperbilirubinemia. Accumulating evidence also shows that genetic polymorphisms linked to hyperbilirubinemia are beneficial against various diseases. In this review article, we first introduce the production, metabolism, and transport of bilirubin. We then discuss the potential benefits of neonatal and adult hyperbilirubinemia. Finally, epigenetic factors as well as metabolomic information associated with hyperbilirubinemia are described. This review article advances the understanding of the physiological importance of the paradoxical compound bilirubin. (Hepatology 2018;67:1609-1619).

Authors: Ryoichi Fujiwara, Mathias Haag, Elke Schaeffeler, Anne T. Nies, Ulrich M. Zanger, Matthias Schwab

Date Published: 1st Apr 2018

Publication Type: Not specified

The formation of estrogen-like tamoxifen metabolites and their influence on enzyme activity and gene expression of ADME genes.

Abstract (Expand)

Tamoxifen, a standard therapy for breast cancer, is metabolized to compounds with anti-estrogenic as well as estrogen-like action at the estrogen receptor. Little is known about the formation of … estrogen-like metabolites and their biological impact. Thus, we characterized the estrogen-like metabolites tamoxifen bisphenol and metabolite E for their metabolic pathway and their influence on cytochrome P450 activity and ADME gene expression. The formation of tamoxifen bisphenol and metabolite E was studied in human liver microsomes and Supersomes. Cellular metabolism and impact on CYP enzymes was analyzed in upcyte(R) hepatocytes. The influence of 5 microM of tamoxifen, anti-estrogenic and estrogen-like metabolites on CYP activity was measured by HPLC MS/MS and on ADME gene expression using RT-PCR analyses. Metabolite E was formed from tamoxifen by CYP2C19, 3A and 1A2 and from desmethyltamoxifen by CYP2D6, 1A2 and 3A. Tamoxifen bisphenol was mainly formed from (E)- and (Z)-metabolite E by CYP2B6 and CYP2C19, respectively. Regarding phase II metabolism, UGT2B7, 1A8 and 1A3 showed highest activity in glucuronidation of tamoxifen bisphenol and metabolite E. Anti-estrogenic metabolites (Z)-4-hydroxytamoxifen, (Z)-endoxifen and (Z)-norendoxifen inhibited the activity of CYP2C enzymes while tamoxifen bisphenol consistently induced CYPs similar to rifampicin and phenobarbital. On the transcript level, highest induction up to 5.6-fold was observed for CYP3A4 by tamoxifen, (Z)-4-hydroxytamoxifen, tamoxifen bisphenol and (E)-metabolite E. Estrogen-like tamoxifen metabolites are formed in CYP-dependent reactions and are further metabolized by glucuronidation. The induction of CYP activity by tamoxifen bisphenol and the inhibition of CYP2C enzymes by anti-estrogenic metabolites may lead to drug-drug-interactions.

Authors: J. Johanning, P. Kroner, M. Thomas, U. M. Zanger, A. Norenberg, M. Eichelbaum, M. Schwab, H. Brauch, W. Schroth, T. E. Murdter

Date Published: 28th Dec 2017

Publication Type: Not specified

Pharmacokinetics and pharmacodynamics of thiopurines in an in vitro model of human hepatocytes: Insights from an innovative mass spectrometry assay.

Abstract (Expand)

AIM: To apply an innovative LC-MS/MS method to quantify thiopurine metabolites in human hepatocytes and to associate them to cytotoxicity. METHODS: Immortalized human hepatocytes (IHH cells) were treated … for 48 and 96 h, with 1.4 x 10(-4) M azathioprine and 1.1 x 10(-3) M mercaptopurine, concentrations corresponding to the IC50 values calculated after 96 h exposure in previous cytotoxicity analysis. After treatments, cells were collected for LC-MS/MS analysis to quantify 11 thiopurine metabolites with different level of phosphorylation and viable cells were counted by trypan blue exclusion assay to determine thiopurines in vitro effect on cell growth and survival. Statistical significance was determined by analysis of variance (ANOVA). RESULTS: Azathioprine and mercaptopurine had a significant time-dependent cytotoxic effect (p-value ANOVA = 0.012), with a viable cell count compared to controls of 55.5% and 67.5% respectively after 48 h and 23.7% and 36.1% after 96 h; no significant difference could be observed between the two drugs. Quantification of thiopurine metabolites evidenced that the most abundant metabolite was TIMP, representing 57.1% and 40.3% of total metabolites after 48 and 96 h. Total thiopurine metabolites absolute concentrations decreased over time: total mean content decreased from 469.9 pmol/million cells to 83.6 pmol/million cells (p-value ANOVA = 0.0070). However, considering the relative amount of thiopurine metabolites, TGMP content significantly increased from 11.4% cells to 26.4% (p-value ANOVA = 0.017). A significant association between thiopurine effects and viable cell counts could be detected only for MeTIMP: lower MeTIMP concentrations were associated with lower cell survival (p-value ANOVA = 0.011). Moreover, the ratio between MeTIMP and TGMP metabolites directly correlated with cell survival (p-value ANOVA = 0.037). CONCLUSION: Detailed quantification of thiopurine metabolites in a human hepatocytes model provided useful insights on the association between thioguanine and methyl-thioinosine nucleotides with cell viability.

Authors: M. Pelin, E. Genova, L. Fusco, M. Marisat, U. Hofmann, D. Favretto, M. Lucafo, A. Taddio, S. Martelossi, A. Ventura, G. Stocco, M. Schwab, G. Decorti

Date Published: 12th Aug 2017

Publication Type: Not specified

Translational learning from clinical studies predicts drug pharmacokinetics across patient populations.

Abstract (Expand)

Early indication of late-stage failure of novel candidate drugs could be facilitated by continuous integration, assessment, and transfer of knowledge acquired along pharmaceutical development programs. … We here present a translational systems pharmacology workflow that combines drug cocktail probing in a specifically designed clinical study, physiologically based pharmacokinetic modeling, and Bayesian statistics to identify and transfer (patho-)physiological and drug-specific knowledge across distinct patient populations. Our work builds on two clinical investigations, one with 103 healthy volunteers and one with 79 diseased patients from which we systematically derived physiological information from pharmacokinetic data for a reference probe drug (midazolam) at the single-patient level. Taking into account the acquired knowledge describing (patho-)physiological alterations in the patient cohort allowed the successful prediction of the population pharmacokinetics of a second, candidate probe drug (torsemide) in the patient population. In addition, we identified significant relations of the acquired physiological processes to patient metadata from liver biopsies. The presented prototypical systems pharmacology approach is a proof of concept for model-based translation across different stages of pharmaceutical development programs. Applied consistently, it has the potential to systematically improve predictivity of pharmacokinetic simulations by incorporating the results of clinical trials and translating them to subsequent studies.

Authors: M. Krauss, U. Hofmann, C. Schafmayer, S. Igel, J. Schlender, C. Mueller, M. Brosch, W. von Schoenfels, W. Erhart, A. Schuppert, M. Block, E. Schaeffeler, G. Boehmer, L. Goerlitz, J. Hoecker, J. Lippert, R. Kerb, J. Hampe, L. Kuepfer, M. Schwab

Date Published: 27th Jun 2017

Publication Type: Not specified

Ligand-dependent and -independent regulation of human hepatic sphingomyelin phosphodiesterase acid-like 3A expression by pregnane X receptor and crosstalk with liver X receptor.

Abstract (Expand)

Pregnane X receptor (PXR) mainly regulates xenobiotic metabolism and detoxification. Additionally, it exerts pleiotropic effects on liver physiology, which in large parts depend on transrepression of … other liver-enriched transcription factors. Based on the hypothesis that lower expression levels of PXR may reduce the extent of this inhibition, an exploratory genome-wide transcriptomic profiling was performed using HepG2 cell clones with different expression levels of PXR. This screen and confirmatory real-time RT-PCR identified sphingomyelin phosphodiesterase acid-like (SMPDL) 3A, a novel nucleotide phosphodiesterase and phosphoramidase, as being up-regulated by PXR-deficiency. Transient siRNA-mediated knock-down of PXR in HepG2 cells and primary human hepatocytes similarly induced mRNA up-regulation, which translated into increased intracellular and secreted extracellular protein levels. Interestingly, ligand-dependent PXR activation also induced SMPDL3A in HepG2 cells and primary human hepatocytes. Electrophoretic mobility shift assays and chromatin immunoprecipitation demonstrated binding of PXR to the previously identified liver X receptor (LXR)-binding DR4 motif as well as to an adjacent ER8 motif in intron 1 of SMPDL3A. Constitutive binding of the unliganded receptor to the intron 1 chromatin indicated ligand-independent repression of SMPDL3A by PXR. Transient transfection and reporter gene analysis confirmed the specific role of these motifs in PXR- and LXR-dependent activation of the SMPDL3A intronic enhancer. PXR inhibited LXR mainly by competition for binding sites. In conclusion, this study describes that a decrease in PXR expression levels and ligand-dependent activation of PXR and LXR increase hepatic SMPDL3A levels, which possibly connects these receptors to hepatic purinergic signaling and phospholipid metabolism and may result in drug-drug interactions with phosphoramidate pro-drugs.

Authors: J. Jeske, A. Bitter, W. E. Thasler, T. S. Weiss, M. Schwab, O. Burk

Date Published: 18th Apr 2017

Publication Type: Not specified

The importance of drug transporter characterization to precision medicine.

Abstract

Not specified

Authors: P. Fisel, A. T. Nies, E. Schaeffeler, M. Schwab

Date Published: 1st Feb 2017

Publication Type: Not specified

Impact of Membrane Drug Transporters on Resistance to Small-Molecule Tyrosine Kinase Inhibitors.

Abstract (Expand)

Small-molecule inhibitors of tyrosine kinases (TKIs) are the mainstay of treatment for many malignancies and represent novel treatment options for other diseases such as idiopathic pulmonary fibrosis. … Twenty-five TKIs are currently FDA-approved and >130 are being evaluated in clinical trials. Increasing evidence suggests that drug exposure of TKIs may significantly contribute to drug resistance, independently from somatic variation of TKI target genes. Membrane transport proteins may limit the amount of TKI reaching the target cells. This review highlights current knowledge on the basic and clinical pharmacology of membrane transporters involved in TKI disposition and their contribution to drug efficacy and adverse drug effects. In addition to non-genetic and epigenetic factors, genetic variants, particularly rare ones, in transporter genes are promising novel factors to explain interindividual variability in the response to TKI therapy.

Authors: C. Neul, E. Schaeffeler, A. Sparreboom, S. Laufer, M. Schwab, A. T. Nies

Date Published: 25th Oct 2016

Publication Type: Not specified

Polymorphic variation in TPMT is the principal determinant of TPMT phenotype: A meta-analysis of three genome-wide association studies.

Abstract (Expand)

Thiopurine-related hematotoxicity in pediatric acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases has been linked to genetically defined variability in thiopurine S-methyltransferase … (TPMT) activity. While gene testing of TPMT is being clinically implemented, it is unclear if additional genetic variation influences TPMT activity with consequences for thiopurine-related toxicity. To examine this possibility, we performed a genome-wide association study (GWAS) of red blood cell TPMT activity in 844 Estonian individuals and 245 pediatric ALL cases. Additionally, we correlated genome-wide genotypes to human hepatic TPMT activity in 123 samples. Only genetic variants mapping to chromosome 6, including the TPMT gene region, were significantly associated with TPMT activity (P < 5.0 x 10-8 ) in each of the three GWAS and a joint meta-analysis of 1,212 cases (top hit P = 1.2 x 10-72 ). This finding is consistent with TPMT genotype being the primary determinant of TPMT activity, reinforcing the rationale for genetic testing of TPMT alleles in routine clinical practice to individualize mercaptopurine dosage.

Authors: R. Tamm, R. Magi, R. Tremmel, S. Winter, E. Mihailov, A. Smid, A. Moricke, K. Klein, M. Schrappe, M. Stanulla, R. Houlston, R. Weinshilboum, I. Mlinaric Rascan, A. Metspalu, L. Milani, M. Schwab, E. Schaeffeler

Date Published: 23rd Oct 2016

Publication Type: Not specified

DNA Methylation of ADME Genes.

Abstract (Expand)

The epigenetic regulation of expression of genes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs contributes to interindividual variability in drug response. Epigenetic … mechanisms include DNA methylation, histone modifications, and miRNAs. This review systematically outlines the influence of DNA methylation on ADME gene expression and highlights the consequences for interindividual variability in drug response or drug-induced toxicity and the implications for personalized medicine.

Authors: P. Fisel, E. Schaeffeler, M. Schwab

Date Published: 12th Apr 2016

Publication Type: Not specified

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