A5044963611- Drug Transport and Resistance Mechanisms
- Pediatric Hepatobiliary Diseases and Treatments
- Dialysis and Renal Disease Management
- Liver Disease Diagnosis and Treatment
- Neonatal Health and Biochemistry
- Acute Lymphoblastic Leukemia research
- Pharmacological Effects and Toxicity Studies
- Cholesterol and Lipid Metabolism
- Central Venous Catheters and Hemodialysis
- Virus-based gene therapy research
- Muscle and Compartmental Disorders
- Chronic Kidney Disease and Diabetes
- Clinical Nutrition and Gastroenterology
- Acute Kidney Injury Research
- Liver Diseases and Immunity
- Renal function and acid-base balance
- Trace Elements in Health
- Pancreatic function and diabetes
- Pharmacogenetics and Drug Metabolism
- Electrolyte and hormonal disorders
- Heme Oxygenase-1 and Carbon Monoxide
- Amino Acid Enzymes and Metabolism
- RNA Interference and Gene Delivery
- Chronic Myeloid Leukemia Treatments
- Gastroesophageal reflux and treatments
Amsterdam University Medical Centers
2019-2025
University of Amsterdam
2015-2025
Amsterdam UMC Location University of Amsterdam
2011-2024
Asser Institute
2015-2020
Biopredic (France)
2016
Amsterdam University of the Arts
2007
Vrije Universiteit Amsterdam
2005
Metabolism and Renal Physiology
1992
Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure this system can lead to buildup conjugated bilirubin in blood, resulting jaundice. The mechanistic basis excretion hyperbilirubinemia syndromes largely understood, but that Rotor syndrome, an autosomal recessive disorder characterized hyperbilirubinemia, coproporphyrinuria, near-absent hepatic uptake anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome...
Organic anion transporting polypeptides (OATPs) are uptake transporters for a broad range of endogenous compounds and xenobiotics. To investigate the physiologic pharmacologic roles OATPs 1A 1B subfamilies, we generated mice lacking all established predicted mouse Oatp1a/1b (referred to as Slco1a/1b-/- mice, SLCO genes encode OATPs). were viable fertile but exhibited markedly increased plasma levels bilirubin conjugated glucuronide unconjugated bile acids. The unexpected hyperbilirubinemia...
The Na + ‐taurocholate cotransporting polypeptide (NTCP) mediates uptake of conjugated bile acids (BAs) and is localized at the basolateral membrane hepatocytes. It has recently been recognized as receptor mediating hepatocyte‐specific entry hepatitis B virus delta virus. Myrcludex B, a peptide inhibitor entry, assumed to specifically target NTCP. Here, we investigated BA transport binding in first Slc10a1 ‐knockout mouse model ( encodes NTCP). Primary Slc10a1−/− hepatocytes showed absence...
The Na + ‐taurocholate cotransporting polypeptide (NTCP/ SLC10A1 ) is believed to be pivotal for hepatic uptake of conjugated bile acids. However, plasma acid levels are normal in a subset NTCP knockout mice and treated with myrcludex B, specific inhibitor. Here, we elucidated which transport proteins mediate the acids demonstrated intestinal sensing elevated mice. Mice or healthy volunteers were B. Hepatic kinetics determined wild‐type (WT), organic anion transporting (OATP) (lacking...
Abstract A nutritional intervention, exclusive enteral nutrition (EEN) can induce remission in patients with pediatric Crohn’s disease (CD). We characterized changes the fecal microbiota and metabolome to identify mechanism of EEN. Feces 43 children were collected prior, during after Microbiota metabolites analyzed by 16S rRNA gene amplicon sequencing NMR. Selected evaluated relevant model systems. CD controls different at all time points. Amino acids, primary bile salts, trimethylamine...
The ATP-binding-cassette (ABC) transporter multidrug resistance protein (MRP) 2 (ABCC2) forms a natural barrier and efflux system for various (conjugates of) drugs, other xenotoxins, endogenous compounds. To obtain insight in the pharmacological physiological functions of Mrp2, we generated <i>Mrp2</i> knockout mice, which were viable fertile but suffered from mild hyperbilirubinemia due to impaired excretion bilirubin monoglucuronides into bile. mice also had an 80-fold decreased biliary...
Mutations in ATP8B1 cause severe inherited liver disease. The disease is characterized by impaired biliary bile salt excretion (cholestasis), but the mechanism whereby function results cholestasis poorly understood. a type 4 P-type ATPase and flippase for phosphatidylserine. Atp8b1-deficient mice display dramatic increase extraction of cholesterol from canalicular (apical) membrane hepatocyte. Here we studied hypothesis that disproportionate impairs activity transporter, ABCB11, as...
MRP2 is an apical transporter expressed in hepatocytes and the epithelial cells of small intestine kidney proximal tubule. It extrudes organic anions, conjugated compounds, some uncharged amphipaths. We studied transport abundant food-derived carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-<i>b</i>]pyridine (PhIP) vitro, using <i>MRP2</i> transfected cell line (MDCK II) intestinal explants from Wistar MRP2-deficient TR<sup>−</sup> rats Ussing chambers. In experiments with line, we could...
MRP3 is an ABC transporter localized in the basolateral membrane of epithelial cells such as hepatocytes and enterocytes. In this study, role Mrp3 drug disposition was investigated. Because preferentially transports glucuronide conjugates, we investigated vivo acetaminophen (APAP) its metabolites. Mrp3+/+ Mrp3-/- knockout mice received APAP (150 mg/kg), bile collected. Basolateral canalicular excretion also assessed isolated perfused liver. separate studies, 400 mg APAP/kg for assessment...
Abstract Background The contribution of individual organs to the whole-body adaptive response fasting has not been established. Hence, gene-expression profiling, pathway, network and gene-set enrichment analysis immunohistochemistry were carried out on mouse liver after 0, 12, 24 72 hours fasting. Results Liver wet weight had declined ~44, ~5, ~11 ~10% per day 24, 48 fasting, respectively. structure metabolic zonation preserved. Supervised hierarchical clustering showed separation between...
Cholyl-l-lysyl-fluorescein (CLF) is a fluorescent bile salt derivative that being developed as an agent for determining in vivo liver function. However, the mechanisms of uptake and excretion by hepatocytes have not been rigorously studied. We directly assessed transport capacity various hepatobiliary transporters CLF. Uptake experiments were performed Chinese hamster ovary cells transfected with human <i>NTCP</i>, <i>OATP1B1</i>, <i>OATP1B3</i>, <i>OATP2B1.</i> Conversely, excretory systems...
The main endogenous source of glutamine is de novo synthesis in striated muscle via the enzyme synthetase (GS). mice which GS selectively but completely eliminated from with Cre-loxP strategy (GS-KO/M mice) are, nevertheless, healthy and fertile. Compared controls, circulating concentration net production across hindquarter were not different fed GS-KO/M mice. Only a approximately 3-fold higher escape ammonia revealed absence muscle. However, after 20 h fasting, able to mount 4-fold increase...
Abstract Purpose: ABCC2 (MRP2) and ABCG2 (BCRP) transport various endogenous exogenous compounds, including many anticancer drugs, into bile, feces, urine. We investigated the possibly overlapping roles of Abcg2 Abcc2 in elimination drug methotrexate (MTX) its toxic metabolite 7-hydroxymethotrexate (7OH-MTX). Experimental Design: generated characterized Abcc2;Abcg2-/- mice, used these to determine MTX 7OH-MTX after i.v. administration 50 mg/kg MTX. Results: Compared with wild-type, plasma...
Transintestinal cholesterol efflux (TICE) provides an attractive target to increase body excretion. At present, the donor responsible for direct delivery of plasma intestine is unknown. In this study, we investigated role HDL in TICE. ATP-binding cassette protein A1 deficient (Abca1−/−) mice that lack and wild-type (WT) were intravenously injected with chylomicron-like emulsion particles contained radiolabeled liberated liver partly reenters circulation. Both groups secreted from into...
Anion exchanger 2 (AE2), the principal bicarbonate secretor in human biliary tree, is down‐regulated primary cholangitis. AE2 creates a “bicarbonate umbrella” that protects cholangiocytes from proapoptotic effects of bile salts by maintaining them deprotonated. We observed knockdown sensitized immortalized H69 to not only salt‐induced apoptosis (BSIA) but also etoposide‐induced apoptosis. Because toxicity etoposide pH‐independent, there could be more general mechanism for sensitization...
Progressive familial intrahepatic cholestasis type 3 (PFIC3), for which there are limited therapeutic options, often leads to end-stage liver disease before adulthood due impaired ABCB4-dependent phospholipid transport bile. Using adeno-associated virus serotype 8 (AAV8)-mediated gene therapy, we aimed restore the content in bile levels that prevent damage, thereby enabling stable hepatic ABCB4 expression and long-term correction of phenotype a murine model PFIC3.Ten-week-old Abcb4-/- mice...
The prevalence of chronic inflammation is high in dialysis patients. Moreover, it associated with an increased mortality risk, yet the origin patients remains unclear. aim this study was to determine effect a hemodialysis session (HD) on C-reactive protein (CRP) levels and relation survival. As part large, prospective, multicenter Netherlands (Netherlands Cooperative Study Adequacy Dialysis), who were started treatment between September 1997 May 1999 included. Demographic data, clinical...
Abstract Glutamine synthetase (GS) is a key enzyme in the “glutamine‐glutamate cycle” between astrocytes and neurons, but its function vivo was thus far tested only pharmacologically. Crossing GS fl/lacZ or fl/fl mice with hGFAP ‐Cre resulted prenatal excision of fl allele astrocytes. “GS‐KO/A” were born without malformations, did not suffer from seizures, had suckling reflex, drink immediately after birth, then gradually failed to feed died on postnatal day 3. Artificial feeding relieved...