Alpha-tocopherol regulation of hepatic cytochrome P450s and ABC transporters in rats.
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.
Mustacich
Debbie J
DJ
Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA.
Leonard
Scott W
SW
Devereaux
Michael W
MW
Sokol
Ronald J
RJ
Traber
Maret G
MG
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D002839:Chromans / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D007279:Injections, Subcutaneous; D008099:Liver / Q000187:drug effects; D008110:Liver Extracts; D008297:Male; D008958:Models, Molecular; D011422:Propionates / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000494:pharmacology*
D018528:ATP-Binding Cassette Transporters; D002839:Chromans; D008110:Liver Extracts; D011422:Propionates; C084852:2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman; D003577:Cytochrome P-450 Enzyme System; D024502:alpha-Tocopherol