ChloroquineV1, France, Analysis, bibRecord, 000458

Uptake, subcellular distribution and biotransformation of 3H-labelled astemizole in cultured rat hepatocytes

Identifieur interne : 000458 ( France/Analysis ); précédent : 000457; suivant : 000459

Uptake, subcellular distribution and biotransformation of 3H-labelled astemizole in cultured rat hepatocytes

Auteurs : Christine Waterkeyn [Belgique] ; Pierre Laduron [Belgique, France] ; Willem Meuldermans [Belgique] ; Andre Trouet [Belgique] ; Yves-Jacques Schneider [Belgique]

Source :

Biochemical Pharmacology [ 0006-2952 ] ; 1987.

RBID : ISTEX:2EEA4848C2AD32299B6B17BE6126F7912F927A79

English descriptors

Teeft :
- Astemizole, Biochem, Biol, Cathepsin, Centrifugation, Chloroquine, Continuous incubation, Culture medium, Cultured hepatocytes, Cytochrome, Different concentrations, Different durations, Differential centrifugation, Endoplasmic reticulum, Equilibration profile, Experimental protocol, Final supernate, Fresh culture medium, Glucuronoconjugated, Glucuronoconjugated metabolites, Hepatocytes, Homogenate, Hplc analysis, Independent experiments, Isopycnic, Isopycnic centrifugation, Kinetic experiments, Lipophilic, Lower densities, Lysosomal enzymes, Lysosome, Major part, Marker enzyme, Marker enzymes, Metabolite, Nadph, Nadph cytochrome, Native astemizole, Particulate fraction, Phospholipid, Receptor, Reductase, Schneider, Subcellular, Subcellular fractions, Sucrose, Sucrose gradients, Trouet, Unconjugated metabolites, Washout.

Abstract

Abstract: When incubated with3H-astemizole, a potent antagonist of H1 receptor, cultured rat hepatocytes, which do not express specific receptors for this ligand, avidly take up 3H-label proportionally to the drug concentration. HPLC analysis indicates that at 10 ng 3H-astemizole/ml, cells almost entirely deplete the culture medium of the drug within 4 hr of incubation. At 37°, astemizole is metabolized and released into the culture medium mainly under the form of glucuronoconjugated metabolites.Differential centrifugation of homogenates from hepatocytes incubated with 3H-astemizole indicates that astemizole and unconjugated metabolites are found in the particulate fraction, whereas astemizole and conjugated metabolites are present in the cytosol. Isopycnic centrifugation on sucrose gradient shows that the major part of the 3H-label in the particulate fraction distributes like phospholipids and NADPH cytochrome c reductase, suggesting an association with membranes and, in particular, with the endoplasmic reticulum.Chloroquine, a drug accumulating within lysosomes and acidic endosomes, decreases the uptake of 3H-astemizole by hepatocytes and induces, during isopycnic centrifugation of a particulate fraction, a shift of the 3H-label towards lower densities where it closely accompanies cathepsin B. This suggests that a minor part of astemizole accumulated in the hepatocytes could be trapped within lysosomes. These results could support the hypothesis that aspecific binding of astemizole to cellular membranes and, to a lesser extent, trapping in lysosomes could play a role in the pharmacokinetics of the drug.

Url:

https://api.istex.fr/ark:/67375/6H6-K1N2PJJS-Z/fulltext.pdf

DOI: 10.1016/0006-2952(87)90571-5

Affiliations:

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ISTEX:2EEA4848C2AD32299B6B17BE6126F7912F927A79

Le document en format XML

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<profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Astemizole</term>
<term>Biochem</term>
<term>Biol</term>
<term>Cathepsin</term>
<term>Centrifugation</term>
<term>Chloroquine</term>
<term>Continuous incubation</term>
<term>Culture medium</term>
<term>Cultured hepatocytes</term>
<term>Cytochrome</term>
<term>Different concentrations</term>
<term>Different durations</term>
<term>Differential centrifugation</term>
<term>Endoplasmic reticulum</term>
<term>Equilibration profile</term>
<term>Experimental protocol</term>
<term>Final supernate</term>
<term>Fresh culture medium</term>
<term>Glucuronoconjugated</term>
<term>Glucuronoconjugated metabolites</term>
<term>Hepatocytes</term>
<term>Homogenate</term>
<term>Hplc analysis</term>
<term>Independent experiments</term>
<term>Isopycnic</term>
<term>Isopycnic centrifugation</term>
<term>Kinetic experiments</term>
<term>Lipophilic</term>
<term>Lower densities</term>
<term>Lysosomal enzymes</term>
<term>Lysosome</term>
<term>Major part</term>
<term>Marker enzyme</term>
<term>Marker enzymes</term>
<term>Metabolite</term>
<term>Nadph</term>
<term>Nadph cytochrome</term>
<term>Native astemizole</term>
<term>Particulate fraction</term>
<term>Phospholipid</term>
<term>Receptor</term>
<term>Reductase</term>
<term>Schneider</term>
<term>Subcellular</term>
<term>Subcellular fractions</term>
<term>Sucrose</term>
<term>Sucrose gradients</term>
<term>Trouet</term>
<term>Unconjugated metabolites</term>
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<front><div type="abstract" xml:lang="en">Abstract: When incubated with3H-astemizole, a potent antagonist of H1 receptor, cultured rat hepatocytes, which do not express specific receptors for this ligand, avidly take up 3H-label proportionally to the drug concentration. HPLC analysis indicates that at 10 ng 3H-astemizole/ml, cells almost entirely deplete the culture medium of the drug within 4 hr of incubation. At 37°, astemizole is metabolized and released into the culture medium mainly under the form of glucuronoconjugated metabolites.Differential centrifugation of homogenates from hepatocytes incubated with 3H-astemizole indicates that astemizole and unconjugated metabolites are found in the particulate fraction, whereas astemizole and conjugated metabolites are present in the cytosol. Isopycnic centrifugation on sucrose gradient shows that the major part of the 3H-label in the particulate fraction distributes like phospholipids and NADPH cytochrome c reductase, suggesting an association with membranes and, in particular, with the endoplasmic reticulum.Chloroquine, a drug accumulating within lysosomes and acidic endosomes, decreases the uptake of 3H-astemizole by hepatocytes and induces, during isopycnic centrifugation of a particulate fraction, a shift of the 3H-label towards lower densities where it closely accompanies cathepsin B. This suggests that a minor part of astemizole accumulated in the hepatocytes could be trapped within lysosomes. These results could support the hypothesis that aspecific binding of astemizole to cellular membranes and, to a lesser extent, trapping in lysosomes could play a role in the pharmacokinetics of the drug.</div>
</front>
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Uptake, subcellular distribution and biotransformation of 3H-labelled astemizole in cultured rat hepatocytes

Uptake, subcellular distribution and biotransformation of 3H-labelled astemizole in cultured rat hepatocytes

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Abstract

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