Modulation of Cyp3a11 mRNA expression by alpha-tocopherol but not gamma-tocotrienol in mice.
Metabolism of vitamin E is initiated by cytochrome P450 (CYP) enzymes usually involved in the metabolism of xenobiotics. Like other CYP substrates, vitamin E induced a reporter gene under the control of the pregnane X receptor (PXR) which regulates the expression of CYPs including CYP3A4. gamma-Tocotrienol, the most effective PXR activator, also induced endogenous CYP3A4 mRNA in HepG2 cells. Since these findings imply an interference of vitamin E with drug metabolism it was deemed necessary to investigate their in vivo relevance. Therefore, mice were grown for 3 months with alpha-tocopherol-deficient, -adequate, and -supranutritional diet, i.e. 2, 20 and 200 mg RRR-alpha-tocopheryl acetate/kg diet, respectively. Half of them received 250 microg gamma-tocotrienol/day for the last 7 days. After 3 months, hepatic levels of Cyp3a11 mRNA, the murine homolog to human CYP3A4, were about 2.5-fold higher in the 20 and 200 mg alpha-tocopherol groups than in the 2 mg group. After feeding 200 mg alpha-tocopherol for 9 months, Cyp3a11 mRNA was 1.7-fold higher than after 3 months. In contrast, gamma-tocotrienol did not induce Cyp3a11 mRNA. This could be explained by its high metabolism as demonstrated by the 20- to 25-fold increase in the urinary excretion of gamma-CEHC, the final metabolite of gamma-tocotrienol degradation. In conclusion, alpha-tocopherol maintains an adequate level of xenobiotic-metabolizing enzymes. If fed in supranutritional dosages, especially for longer times, alpha-tocopherol induces Cyp3a11 to levels which might interfere with drug metabolism.
Kluth
Dirk
D
Department of Biochemistry of Micronutrients, German Institute of Human Nutrition, Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany.
Landes
Nico
N
Pfluger
Paul
P
Müller-Schmehl
Katrin
K
Weiss
Kathrin
K
Bumke-Vogt
Christiane
C
Ristow
Michael
M
Brigelius-Flohé
Regina
R
D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D024502:alpha-Tocopherol / Q000378:metabolism / Q000494:pharmacology*; D024504:gamma-Tocopherol / Q000378:metabolism / Q000494:pharmacology*
D012333:RNA, Messenger; D024504:gamma-Tocopherol; D024502:alpha-Tocopherol