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J. Biol. Chem., Vol. 277, Issue 28, 25290-25296, July 12, 2002
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From the Division of Nutritional Sciences, Cornell University,
Ithaca, New York 14853
Postabsorptive elimination of the various forms
of vitamin E appears to play a key role in regulation of tissue
tocopherol concentrations, but mechanisms of tocopherol metabolism have
not been elucidated. Here we describe a pathway involving cytochrome P450-mediated
Cytochrome P450
-Hydroxylase Pathway of Tocopherol
Catabolism
NOVEL MECHANISM OF REGULATION OF VITAMIN E STATUS*
-hydroxylation of the tocopherol phytyl side chain followed by stepwise removal of two- or three-carbon moieties, ultimately yielding the 3'-carboxychromanol metabolite that is excreted
in urine. All key intermediates of 
-tocopherol metabolism via this
pathway were identified in hepatocyte cultures using gas
chromatography-mass spectrometry. NADPH-dependent synthesis of the initial - and 
-tocopherol 13'-hydroxy and -carboxy
metabolites was demonstrated in rat and human liver microsomes.
Functional analysis of several recombinant human liver P450 enzymes
revealed that tocopherol--hydroxylase activity was associated only
with CYP4F2, which also catalyzes -hydroxylation of leukotriene
B4 and arachidonic acid. Tocopherol--hydroxylase
exhibited similar binding affinities but markedly higher catalytic
activities for -tocopherol than -tocopherol, suggesting a role
for this pathway in the preferential physiological retention of
-tocopherol and elimination of -tocopherol. Sesamin potently
inhibited tocopherol--hydroxylase activity exhibited by CYP4F2 and
rat or human liver microsomes. Since dietary sesamin also results in
elevated tocopherol levels in vivo, this pathway appears to
represent a functionally significant means of regulating vitamin E status.
*
This work was supported by Grant 9800692 from the
United States Department of Agriculture/National Research
Initiative Competitive Grants Program and National Institutes of Health
Training Grant DK07158-25 (to T. J. S.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Division of
Nutritional Sciences, Cornell University, 113 Savage Hall, Ithaca, NY
14853. Tel.: 607-255-2661; Fax: 607-255-1033; E-mail:
rsp3@cornell.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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