Biliary secretion of alpha-tocopherol and the role of the mdr2 P-glycoprotein in rats and mice.

TitleBiliary secretion of alpha-tocopherol and the role of the mdr2 P-glycoprotein in rats and mice.
Publication TypeJournal Article
Year of Publication1998
AuthorsMustacich DJ, Shields J, Horton RA, Brown MK, Reed DJ
JournalArchives of biochemistry and biophysics
Volume350
Issue2
Pagination183-92
Date Published1998 Feb 15
ISSN0003-9861
KeywordsAnimals, ATP-Binding Cassette Transporters, Bile, Bile Acids and Salts, Carbon Radioisotopes, Female, Glutathione, Glutathione Disulfide, Liver, Male, Mice, Mice, Knockout, P-Glycoprotein, P-Glycoproteins, Phosphatidylcholines, Piperonyl Butoxide, Rats, Rats, Sprague-Dawley, Verapamil, Vitamin E
Abstract

The mechanism by which alpha-tocopherol (alpha-T) is secreted into the bile is not known; however, we have previously demonstrated that treatment with piperonyl butoxide (PIP, 1 g/kg) results in increased biliary output of both alpha-T and phosphatidylcholine within 3 h of ip injection in rats and that the biliary output of both substances was prevented by chemicals that disrupt microtubules (Toxicol. Appl. Pharmacol. 139, 411-417 (1996)). The P-glycoprotein (Pgp) encoded by the mdr2 gene has been shown to transport phosphatidylcholine into the bile; therefore, in the current study, we utilized the Pgp inhibitor verapamil to investigate the possible involvement of Pgps in the biliary secretion of alpha-T. When rats were iv injected with verapamil (4 mg/kg) 10 min prior to PIP treatment, verapamil prevented the PIP-induced increases in biliary alpha-T and phosphatidylcholine output and resulted in biliary alpha-T outputs that were significantly less than controls. Also, we determined that the biliary alpha-T levels in mdr2 knockout mice were 25% of those in wildtype mice; furthermore, mdr2 liver, lung, and kidney levels of alpha-T and glutathione differed from those of wildtype. To investigate the fate of biliary alpha-T, we injected 14C-labeled alpha-T into the bile duct cannulae of rats and determined that approximately 60% of the radioactivity was reabsorbed within 1 h. Our results indicate that alpha-T undergoes enterohepatic circulation and that the biliary secretion of alpha-T, basally and following chemical treatment, is dependent on the presence of a functioning mdr2 Pgp in rats and mice.

DOI10.1006/abbi.1997.0529
Alternate JournalArch. Biochem. Biophys.