Biomedical subjects

R Oude Elferink

Publications and source records attributed to R Oude Elferink.

5 recordsLinked to original sources

PubMed2003

Cholestasis.

In contrast with urine formation, bile flow is not dependent on hydrostatic forces, but driven by osmotic pressure of solutes secreted across the apical membrane of hepatocytes and bile duct epithelial cells. This secretory process is mediated by a set of primary active transporters that use ATP hydrolysis to pump solutes against the concentration gradient. The most important solutes in bile are bile salts, lipids, electrolytes, and organic anions. The direct consequence of the osmotic mechanism of bile formation is that impaired function of these pumps leads to impaired bile flow-that is, cholestasis. The function of these pumps is highlighted by a number of inherited cholestatic diseases, which are caused by mutations in these genes. Identification of the molecular defect in these diseases was not only important for diagnostic reasons but also emphasised that impaired transporter function has pathological consequences. Indeed, it is now becoming clear that impaired or downregulated transporter function is also involved in the pathogenesis of acquired cholestatic syndromes.

Bile↗

PubMed2001

Mammalian ABC transporters in health and disease.

The ATP-binding cassette (ABC) transporters are a family of large proteins in membranes and are able to transport a variety of compounds through membranes against steep concentration gradients at the cost of ATP hydrolysis. The available outline of the human genome contains 48 ABC genes; 16 of these have a known function and 14 are associated with a defined human disease. Major physiological functions of ABC transporters include the transport of lipids, bile salts, toxic compounds, and peptides for antigen presentation or other purposes. We review the functions of mammalian ABC transporters, emphasizing biochemical mechanisms and genetic defects. Our overview illustrates the importance of ABC transporters in human physiology, toxicology, pharmacology, and disease. We focus on three topics: (a) ABC transporters transporting drugs (xenotoxins) and drug conjugates. (b) Mammalian secretory epithelia using ABC transporters to excrete a large number of substances, sometimes against a steep concentration gradient. Several inborn errors in liver metabolism are due to mutations in one of the genes for these pumps; these are discussed. (c) A rapidly increasing number of ABC transporters are found to play a role in lipid transport. Defects in each of these transporters are involved in human inborn or acquired diseases.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2000

Endotoxin-induced mortality in bile duct-ligated rats after administration of reconstituted high-density lipoprotein.

Cholestatic patients have substantial morbidity because of increased susceptibility to endotoxin (lipopolysaccharide [LPS]). Although reconstituted high-density lipoprotein (rHDL) can bind and neutralize LPS, cholestasis is associated with a near complete absence of HDL. Effects of rHDL infusion on the outcome of LPS-induced inflammatory responses in cholestatic rats were determined. Bile duct-ligated (BDL) and sham rats were treated with rHDL or saline and challenged with LPS. Distribution of cholesterol over the lipoprotein subclasses changed by ligation: levels in low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) were increased 2-fold and 5-fold, respectively, and were decreased in HDL 2-fold. rHDL treatment did not affect cholesterol distribution. LPS was mainly found in the HDL fraction, and ligation affected only levels of HDL-bound LPS (50% decrease; P<.05). Although rHDL infusion effectively normalized the lipoprotein-bound LPS distribution, it resulted in increased sensitivity (mortality: 88% in the ligation + rHDL group versus 44% in the ligation + saline group, 25% in the sham + saline group, and 0% in the sham + rHDL group, P <.05). In accordance with these results, plasma tumor necrosis factor (TNF) was significantly highest in the BDL + rHDL group at several hours after LPS challenge as well as the accumulation of LPS in the liver (P<.05). rHDL infusion leads to increased LPS-induced mortality in cholestatic rats. These results sharply contrast with the protective effects of rHDL suppletion in experimental endotoxemia in animals and human volunteers without biliary obstruction and suggest that there may be danger in administration of rHDL to cholestatic patients.

Animals↗

PubMed1993

Assignment of the human UDP glucuronosyltransferase gene (UGT1A1) to chromosome region 2q37.

UDP glucuronosyltransferases (UGTs) comprise a multigene family of drug-metabolizing enzymes. The sub-family of UGTs that conjugate bilirubin and phenolic compounds with glucuronic acid has been termed UGT1A1. In man, UGT1A1 isoforms are encoded by a single gene, UGT1A1. Protein isoforms encoded by UGT1A1 originate by alternative splicing. In the present study, we used the cDNA of UGT1A1*4, a bilirubin-conjugating isoform, to localize the UGT1A1 locus in the human genome. The UGT1A1 gene was assigned by in situ hybridization to chromosome region 2q37.

Chromosome Mapping↗

PubMed1982

Biosynthesis of acid alpha-glucosidase in late-onset forms of glycogenosis type II (Pompe's disease).

Cultured human skin fibroblasts from control persons and from patients with the generalized and late-onset forms of Pompe's disease were labelled with radioactive leucine and the incorporation of radioactivity into acid alpha-glucosidase and cathepsin D was analysed by immunoprecipitation, gel electrophoresis and fluorography. When the labelling was carried out for 6-12 h in the presence of NH4Cl, the labelling of secreted alpha-glucosidase relative to that of secreted cathepsin D in fibroblasts from patients with the late-onset form of Pompe's disease was less than 15% of that in fibroblasts from control persons. However, when the fibroblasts were labelled for less than 1 h, the relative rate of incorporation of radioactivity into acid alpha-glucosidase was rather similar in the two types of fibroblasts. In fibroblasts from patients with the generalized form of Pompe's disease no incorporation of radioactivity into acid alpha-glucosidase could be detected.

Cathepsin D↗