Influence of luminal monosaccharides on secretion of glutathione conjugates from rat small intestine in vitro.
Intestinal efflux transporters can significantly reduce the absorption of the drug after peroral application. In this work we studied secretion of glutathione conjugates triggered by glucose at the luminal side of the intestine. Glucose stimulated secretion of DNPSG, NEMSG and CDNB. We used some different monosaccharides and determined that glucose, galactose and alpha-methylglucopyranoside trigger the secretion, while mannitol and fructose do not. We concluded that interaction with SGLT transporter is the key process necessary for this triggering. To determine which of possible glutathione conjugate transporters (MRP2, MRP4, BCRP or RLIP76) is responsible for the secretion of glutathione conjugates, we used benzbromarone, a MRP inhibitor, and sulfanitran and furosemide, two allosteric MRP2 activators. Benzbromarone inhibited glucose stimulated DNPSG secretion, while allosteric activators additionally increased the secretion. We concluded that MRP2 transporter is related to glucose stimulated DNPSG secretion. Regarding the work of Kubitz et al. we tested the effect of changed medium osmolarity on DNPSG transport and determined that hypoosmolar conditions trigger secretion of DNPSG. These findings suggest that intestinal MRP2 activity has no basal level, but can be stimulated by hypoosmolarity and SGLT transport.
Krka d.d., Novo mesto, Smarjeska cesta 6, 8501 Novo mesto, Slovenia.
Darko
D
Ursic
Katja
K
Berginc
Simon
S
Zakelj
Albin
A
Kristl
D018528:ATP-Binding Cassette Transporters / Q000819:agonists / Q000037:antagonists & inhibitors; D000818:Animals; D001553:Benzbromarone / Q000378:metabolism; D016764:Cell Polarity; D004137:Dinitrochlorobenzene / Q000378:metabolism; D020895:Enterocytes / Q000378:metabolism; D005665:Furosemide / Q000378:metabolism; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000378:metabolism*; D008297:Male; D049990:Membrane Transport Modulators / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D008757:Methylglucosides / Q000008:administration & dosage / Q000378:metabolism; D009005:Monosaccharides / Q000008:administration & dosage / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000819:agonists / Q000037:antagonists & inhibitors; D009994:Osmolar Concentration; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D055571:Secretory Pathway / Q000187:drug effects / Q000502:physiology*; D051247:Sodium-Glucose Transport Proteins / Q000378:metabolism; D013388:Succinimides / Q000378:metabolism; D013424:Sulfanilamides / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D001553:Benzbromarone; D004137:Dinitrochlorobenzene; D005665:Furosemide; D005947:Glucose; D005978:Glutathione; D005982:Glutathione Transferase; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D008757:Methylglucosides; D009005:Monosaccharides; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051247:Sodium-Glucose Transport Proteins; D013388:Succinimides; D013424:Sulfanilamides; C042630:1-chloro-2,4-dinitrobenzene-glutathione conjugate; C423013:Abcc2 protein, rat; C489542:Abcc4 protein, rat; C086860:glutathione transporter; C064530:N-ethylsuccinimido-S-glutathione; C030190:S-(2,4-dinitrophenyl)glutathione; C009349:sulfanitran