Alpha-tocopherol beta-oxidation localized to rat liver mitochondria.
Approximately 40% of Americans take dietary supplements, including vitamin E (alpha-tocopherol). Unlike other fat-soluble vitamins, alpha-tocopherol is not accumulated to toxic levels. Rather tissue levels are tightly regulated, in part via increased hepatic metabolism and excretion that could, theoretically, alter metabolism of drugs, environmental toxins, and other nutrients. To date, in vivo subcellular location(s) of alpha-tocopherol metabolism have not been identified. The proposed pathway of alpha-tocopherol metabolism proceeds via omega-hydroxylation to 13'-OH-alpha-tocopherol, followed by successive rounds of beta-oxidation to form alpha-CEHC. To test the hypothesis that alpha-tocopherol omega-hydroxylation occurs in microsomes while beta-oxidation occurs in peroxisomes, rats received daily injections of vehicle, 10 mg alpha-tocopherol, or 10 mg trolox/100 g body wt for 3 days, and then microsomes, mitochondria, and peroxisomes were isolated from liver homogenates. Homogenate alpha-tocopherol levels increased 16-fold in alpha-tocopherol-injected rats, while remaining unchanged in trolox- or vehicle-injected rats. Total alpha-tocopherol recovered in the three subcellular fractions represented 93+/-4% of homogenate alpha-tocopherol levels. In alpha-tocopherol-injected rats, microsome alpha-tocopherol levels increased 28-fold, while mitochondria and peroxisome levels increased 8- and 3-fold, respectively, indicating greater partitioning of alpha-tocopherol to the microsomes with increasing liver alpha-tocopherol. In alpha-tocopherol-injected rats, microsome 13'-OH-alpha-tocopherol levels increased 24-fold compared to controls, and were 7-fold greater than 13'-OH-alpha-tocopherol levels in peroxisome and mitochondrial fractions of alpha-tocopherol-injected rats. An unexpected finding was that alpha-CEHC, the end product of alpha-tocopherol metabolism, was found almost exclusively in mitochondria. These data are the first to indicate a mitochondrial role in alpha-tocopherol metabolism.
Mustacich
Debbie J
DJ
Linus Pauling Institute, 571 Weniger Hall, Oregon State University, Corvallis, OR 97331, USA. debbie.mustacich@oregonstate.edu
Leonard
Scott W
SW
Patel
Neha K
NK
Traber
Maret G
MG
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002839:Chromans / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D007279:Injections, Subcutaneous; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; C489272:Abcd3 protein, rat; D002839:Chromans; D050994:Voltage-Dependent Anion Channels; D019362:Cytochrome P-450 CYP2B1; D024502:alpha-Tocopherol; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid