Alpha-tocopherol regulation of hepatic cytochrome P450s and ABC transporters in rats.

TitleAlpha-tocopherol regulation of hepatic cytochrome P450s and ABC transporters in rats.
Publication TypeJournal Article
Year of Publication2006
AuthorsMustacich DJ, Leonard SW, Devereaux MW, Sokol RJ, Traber MG
JournalFree radical biology & medicine
Volume41
Issue7
Pagination1069-78
Date Published2006 Oct 1
ISSN0891-5849
Keywordsalpha-Tocopherol, Animals, ATP-Binding Cassette Transporters, Chromans, Cytochrome P-450 Enzyme System, Injections, Subcutaneous, Liver, Liver Extracts, Male, Models, Molecular, Propionates, Rats, Rats, Sprague-Dawley, Time Factors
Abstract

To test the hypothesis that supra-elevated hepatic alpha-tocopherol concentrations would up-regulate mechanisms that result in increased hepatic alpha-tocopherol metabolism and excretion, rats received daily subcutaneous alpha-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 alpha-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). alpha-Tocopherol metabolites and their intermediates increased and decreased similarly to alpha-tocopherol albeit at lower concentrations. There were no changes in known vitamin E regulatory proteins, i.e., hepatic alpha-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 alpha-tocopherol concentrations, a protein involved in biliary xenobiotic excretion, p-glycoprotein, increased at Day 9, doubling by Day 15. Thus hepatic alpha-tocopherol concentrations altered hepatic proteins involved in metabolism and disposition of xenobiotic agents.

Alternate JournalFree Radic. Biol. Med.