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
Date Published1998 Feb 15
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

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.

Alternate JournalArch. Biochem. Biophys.