Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA.
Free Radic Biol Med. 2011 Dec 1;51(11):2031-40. doi: 10.1016/j.freeradbiomed.2011.08.033. Epub 2011 Sep 3.
The role of hepatic xenobiotic regulatory mechanisms in modulating hepatic α-tocopherol concentrations during excess vitamin E administration remains unclear. We hypothesized that increased hepatic α-tocopherol would cause a marked xenobiotic response. Thus, we assessed cytochrome P450 oxidation systems (phase I), conjugation systems (phase II), and transporters (phase III) after daily α-tocopherol injections (100mg/kg body wt) for up to 9days in rats. α-Tocopherol injections increased hepatic α-tocopherol concentrations nearly 20-fold, along with a 10-fold increase in the hepatic α-tocopherol metabolites α-CEHC and α-CMBHC. Expression of phase I (CYP3A2, CYP3A1, CYP2B2) and phase II (SULT2A1) proteins and/or mRNAs was variably affected by α-tocopherol injections; however, expression of phase III transporter genes was consistently changed by α-tocopherol. Two liver efflux transporter genes, ABCB1b and ABCG2, were up-regulated after α-tocopherol injections, whereas OATP, a liver influx transporter, was down-regulated. Thus, an overload of hepatic α-tocopherol increases its own metabolism and increases expression of genes of transporters that are postulated to lead to increased excretion of both vitamin E and its metabolites.
肝外源性物质调节机制在调节过量维生素 E 给药期间肝 α-生育酚浓度中的作用尚不清楚。我们假设增加肝 α-生育酚会引起明显的外源性物质反应。因此，我们在大鼠中每天注射 α-生育酚（100mg/kg 体重），最多 9 天，评估细胞色素 P450 氧化系统（I 期）、结合系统（II 期）和转运蛋白（III 期）。α-生育酚注射使肝 α-生育酚浓度增加近 20 倍，同时肝 α-生育酚代谢物 α-CEHC 和 α-CMBHC 的浓度增加 10 倍。α-生育酚注射对 I 期（CYP3A2、CYP3A1、CYP2B2）和 II 期（SULT2A1）蛋白和/或 mRNA 的表达有不同程度的影响；然而，α-生育酚一致改变了 III 期转运蛋白基因的表达。两种肝外排转运蛋白基因 ABCB1b 和 ABCG2 在 α-生育酚注射后上调，而 OATP，一种肝内流转运蛋白，下调。因此，肝 α-生育酚的超负荷增加了其自身的代谢，并增加了被推测导致维生素 E 及其代谢物排泄增加的转运蛋白基因的表达。
