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

The role of hepatic xenobiotic regulatory mechanisms in modulating hepatic alpha-tocopherol concentrations during excess vitamin E administration remains unclear. We hypothesized that increased hepatic alpha-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 alpha-tocopherol injections (100 mg/kg body wt) for up to 9 days in rats. alpha-Tocopherol injections increased hepatic alpha-tocopherol concentrations nearly 20-fold, along with a 10-fold increase in the hepatic alpha-tocopherol metabolites alpha-CEHC and alpha-CMBHC. Expression of phase 1 (CYP3A2, CYP3A1, CYP2B2) and phase II (SULT2A1) proteins and/or mRNAs was variably affected by alpha-tocopherol injections; however, expression of phase III transporter genes was consistently changed by alpha-tocopherol. Two liver efflux transporter genes, ABCB1b and ABCG2, were up-regulated after alpha-tocopherol injections, whereas OATP, a liver influx transporter, was down-regulated. Thus, an overload of hepatic alpha-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. (C) 2011 Elsevier Inc. All rights reserved.