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

被引:52
作者
Mustacich, DJ [1 ]
Shields, J [1 ]
Horton, RA [1 ]
Brown, MK [1 ]
Reed, DJ [1 ]
机构
[1] Oregon State Univ, Dept Biochem & Biophys, Corvallis, OR 97331 USA
关键词
vitamin E; piperonyl butoxide; P-glycoprotein; verapamil; bile; phosphatidylcholine; mdr2; glutathione;
D O I
10.1006/abbi.1997.0529
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 these of wildtype. To investigate the fate of biliary alpha-T, we injected C-14-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. (C) 1998 Academic Press.
引用
收藏
页码:183 / 192
页数:10
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