α-Tocopherol injections in rats up-regulate hepatic ABC transporters, but not cytochrome P450 enzymes

Free Radic Biol Med. 2011 Dec 1;51(11):2031-40. doi: 10.1016/j.freeradbiomed.2011.08.033. Epub 2011 Sep 3.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Cytochrome P-450 Enzyme System / metabolism*
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • alpha-Tocopherol / administration & dosage*
  • alpha-Tocopherol / metabolism

Substances

  • ATP-Binding Cassette Transporters
  • Cytochrome P-450 Enzyme System
  • alpha-Tocopherol