A5041194172- Pharmacogenetics and Drug Metabolism
- Drug Transport and Resistance Mechanisms
- Cancer therapeutics and mechanisms
- Advanced Proteomics Techniques and Applications
- Mass Spectrometry Techniques and Applications
- Bioactive Compounds and Antitumor Agents
- Drug-Induced Hepatotoxicity and Protection
- Eicosanoids and Hypertension Pharmacology
- Genomics, phytochemicals, and oxidative stress
- Molecular Biology Techniques and Applications
- Cancer Treatment and Pharmacology
- Synthesis and biological activity
- Metabolomics and Mass Spectrometry Studies
- Carcinogens and Genotoxicity Assessment
- Pediatric Hepatobiliary Diseases and Treatments
- Microtubule and mitosis dynamics
- Pharmacological Effects and Toxicity Studies
- Computational Drug Discovery Methods
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Glioma Diagnosis and Treatment
- Alkaline Phosphatase Research Studies
- Alcohol Consumption and Health Effects
- Hyperglycemia and glycemic control in critically ill and hospitalized patients
- HIV/AIDS drug development and treatment
- Acute Lymphoblastic Leukemia research
Signatope GmbH (Germany)
2018-2025
Natural and Medical Sciences Institute
2017-2021
University of Tübingen
2016-2021
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
2018
Uppsala University
2018
Active Biotech (Sweden)
2018
Many different methods are used for mass-spectrometry-based protein quantification in pharmacokinetics and systems pharmacology. It has not been established to what extent the results from these various comparable. Here, we compared six mass spectrometry-based proteomics by measuring expression of clinically relevant drug transporters metabolizing enzymes human liver. Mean concentrations were general quantified similar levels using whole tissue lysates. Methods subcellular membrane...
Abstract Most drugs and xenobiotics are metabolized in the liver. Amongst others, different cytochrome P450 (CYP) enzymes catalyze metabolic conversion of foreign compounds, various transport proteins engaged excretion metabolites from hepatocytes. Inter-species inter-individual differences hepatic levels activities drug-metabolizing transporters result genetic as well environmental factors, play a decisive role determining pharmacokinetic properties compound given test system. To allow for...
Primary human hepatocytes (PHHs) have been the gold standard in vitro model for liver and are crucial to predict hepatic drug–drug interactions. The aim of this work was assess utility 3D spheroid PHHs study induction important cytochrome P450 (CYP) enzymes drug transporters. from three different donors were treated 4 days with rifampicin, dicloxacillin, flucloxacillin, phenobarbital, carbamazepine, efavirenz, omeprazole, or β‐naphthoflavone. Induction CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9,...
Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants produced by incomplete combustion of organic matter. They induce their own metabolism upregulating xenobiotic-metabolizing enzymes such as cytochrome P450 monooxygenase 1A1 (CYP1A1) activating the aryl hydrocarbon receptor (AHR). However, previous studies showed that individual PAHs may also interact with constitutive androstane (CAR). Here, we studied ten PAHs, different in carcinogenicity classification, for potential to...
The quantification of drug metabolizing enzymes and transporters has recently been revolutionized on the basis targeted proteomic approaches. Isotope-labeled peptides are used as standards for corresponding proteins in enzymatically fragmented samples. However, hurdles these approaches low throughput tedious sample prefractionation steps prior to mass spectrometry (MS) readout. We have developed an assay platform using sensitive selective immunoprecipitation coupled with spectrometric...
Paclitaxel‐induced peripheral neuropathy (PIPN) is a common and dose‐limiting adverse event. The role of P‐glycoprotein (P‐gp) in the neuronal efflux paclitaxel was assessed using translational approach. SH‐SY5Y cells were differentiated to neurons toxicity absence presence P‐gp inhibitor determined. Paclitaxel caused marked dose‐dependent SH‐SY5Y‐derived neurons. neurotoxicity exacerbated with concomitant inhibition by valspodar verapamil, consistent increased intracellular accumulation...
Okadaic acid (OA) is an algae-produced lipophilic marine biotoxin that accumulates in the fatty tissue of filter-feeding shellfish. Ingestion contaminated shellfish leads to diarrheic poisoning syndrome. Furthermore, several other effects OA like genotoxicity, liver toxicity and tumor-promoting properties have been observed, probably linked phosphatase-inhibiting toxin. It has shown at high doses can disrupt physical barrier intestinal epithelium. As intestine do not only constitute a...
and Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) constitutes a significant health problem due to the increasing prevalence lack of therapies for treatment prevention. While pivotal routine cancer treatment, paclitaxel vincristine frequently cause CIPN impact quality life among patients survivors. Here, we investigate molecular mechanisms drug transport in CIPN.
Flucloxacillin is a widely used antibiotic. It an agonist to the nuclear receptor PXR that regulates expression of cytochrome P450 (CYP) enzymes. Treatment with flucloxacillin reduces warfarin efficacy and plasma concentrations tacrolimus, voriconazole, repaglinide. We conducted translational study investigate if induces CYP also investigated its own metabolism as autoinducer. performed randomized, unblinded, two‐period, cross‐over, clinical pharmacokinetic cocktail study. Twelve healthy...
Cholangiocarcinomas (CCAs) are cancers originated in the biliary tree, which characterized by their high mortality and marked chemoresistance, partly due to activity of ATP-binding cassette (ABC) export pumps, whose inhibition has been proposed as a strategy for enhancing response chemotherapy. We have previously shown that β-caryophyllene oxide (CRYO) acts chemosensitizer hepatocellular carcinoma inhibiting ABCB1, MRP1, MRP2. Here, we evaluated usefulness CRYO BCRP improving CCA antitumor...
We aimed to assess if dicloxacillin/flucloxacillin reduces the therapeutic efficacy of direct oral anticoagulants (DOACs) and underlying molecular mechanism.
Aims Dicloxacillin is used to treat staphylococcal infections and we have previously shown that dicloxacillin an inducer of cytochrome P450 enzymes (CYPs). Here, employed a translational approach investigate the effect treatment with on warfarin efficacy in Danish registries. Furthermore, assessed as CYPs vitro. Methods We conducted register‐based study analysed international normalized ratio (INR) levels chronic users before after short‐ long‐term use ( n = 1023) flucloxacillin 123)....
Pre-SARS-CoV-2, tuberculosis was the leading cause of death by a single pathogen. Repetitive exposure Mycobacterium tuberculosis(Mtb) supported development multidrug- and extensively drug-resistant strains, demanding novel drugs. Hyperforin, natural type A polyprenylated polycyclic acylphloroglucinol from St. John's wort, exhibits antidepressant antibacterial effects also against Mtb. Yet, Hyperforin's instability limits utility in clinical practice. Here, we present photo- bench-stable B...
Abstract Activation of the constitutive androstane receptor (CAR) may induce adaptive but also adverse effects in rodent liver, including induction drug-metabolizing enzymes, transient hepatocellular proliferation, and promotion liver tumor growth. Human relevance CAR-related hepatic is controversially debated. Here, we used chimeric FRG-KO mouse model with livers largely repopulated by human hepatocytes, order to study hepatocytes their response treatment CAR activator phenobarbital (PB)...
Multitransmembrane proteins are notoriously difficult to analyze. To date, rapid, and cost-efficient detection methods lacking only mass spectrometry-based systems allow reliable quantification of these proteins. Here, we present a novel type sandwich immunoassay that is capable sensitively detecting multidrug resistance protein 1 (MDR1), prototypic 12-transmembrane-domains transporter. In first assay step, complex samples enzymatically fragmented into peptides as routinely done for...
Detection of mixture effects is a major challenge in current experimental and regulatory toxicology. Robust markers are needed that easy to quantify responsive chemical stressors broad dose range. Several hepatic enzymes proteins related drug metabolism like cytochrome-P-450 (CYP) transporters have been shown be pesticide active substances range therefore good candidates used as for toxicity. Even though they can well quantified at the mRNA level, quantification on protein level challenging...
1,2-unsaturated pyrrolizidine alkaloids (PAs) are secondary plant metabolites that found in many species throughout the world. They of concern for risk assessment as consumption contaminated foodstuff can cause severe liver damage. Of late, transporter-mediated uptake and transport has advanced a vital determinant PA toxicity. In this study, authors investigate PAs its implications toxicity.We show transporter expression levels significantly affected by treatment with senecionine (Sc)...
Triazole fungicides such as propiconazole (Pi) or tebuconazole (Te) show hepatotoxicity in vivo, e.g., hypertrophy and vacuolization of liver cells following interaction with nuclear receptors PXR (pregnane-X-receptor) CAR (constitutive androstane receptor). Accordingly, azoles affect gene expression associated these adverse outcomes vivo but also human vitro. Additionally, genes indicative cholestasis are affected We therefore analyzed the capability Pi Te to cause an outcome pathway...