α-Tocopherol regulation of hepatic cytochrome P450s and ABC transporters in rats

To test the hypothesis that supra-elevated hepatic α-tocopherol concentrations would up-regulate mechanisms that result in increased hepatic α-tocopherol metabolism and excretion, rats received daily subcutaneous α-tocopherol injections (10 mg/100 g body wt) and then were sacrificed on Day 0 or 12 h following their previous injection on Days 3, 6, 9, 12, 15, and 18. Liver α-tocopherol concentrations increased from 12 ± 1 nmol/g (mean ± SE) to 819 ± 74 (Day 3), decreased at Day 9 (486 ± 67), and continued to decrease through Day 18 (338 ± 37). α-Tocopherol metabolites and their intermediates increased and decreased similarly to α-tocopherol albeit at lower concentrations. There were no changes in known vitamin E regulatory proteins, i.e., hepatic α-tocopherol transfer protein or cytochrome P450 (CYP) 4F. In contrast, both CYP3A and CYP2B, key xenobiotic metabolizing enzymes, doubled by Day 6 and remained elevated, while P450 reductase increased more slowly. Consistent with the decrease in liver α-tocopherol concentrations, a protein involved in biliary xenobiotic excretion, p-glycoprotein, increased at Day 9, doubling by Day 15. Thus hepatic α-tocopherol concentrations altered hepatic proteins involved in metabolism and disposition of xenobiotic agents.