J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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A more recent version of this article appeared on May 1, 2007

Papers In Press, published online ahead of print February 6, 2007
J. Lipid Res., doi:10.1194/jlr.M600514-JLR200
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Submitted on December 4, 2006
Revised on January 19, 2007
Accepted on February 5, 2007

Comparative influence of major structural features of tocopherols and tocotrienols on kinetics of their omega -oxidation by cellular and microsomal tocopherol-omega -hydroxylase

Timothy J. Sontag and Robert S. Parker

Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853

Corresponding Author: RSP3{at}CORNELL.EDU

Human cytochrome-P450 4F2 catalyzes the initial omega -hydroxylation reaction in the metabolism of tocopherols and tocotrienols to carboxychromanols and is to date the only enzyme shown to metabolize vitamin E. The objective of this study was to characterize this activity, particularly the influence of key features of tocochromanol substrate structure. The influence of number and position of methyl groups on the chromanol ring, and of stereochemistry and saturation of the side chain, were explored using HepG2 cultures and microsomal reaction systems. Human liver microsomes and microsomes selectively expressing recombinant human CYP4F2 exhibited substrate activity patterns similar to that of HepG2 cells. While activity was strongly associated with substrate accumulation by cells or microsomes, substantial differences in specific activities between substrates remained under conditions of similar microsomal membrane substrate concentration. Methylation at C5 of the chromanol ring was associated with markedly low activity. Tocotrienols exhibited much higher Vmax values than their tocopherol counterparts. Side chain stereochemistry had no effect on omega -hydroxylation of alpha -tocopherol by any system. Kinetic analysis of microsomal CYP4F2 activity revealed Michaelis-Menten kinetics for alpha -TOH, but allosteric cooperativity for other vitamers, especially tocotrienols. Additionally, alpha -tocopherol was a positive effector of omega -hydroxylation of other vitamers. These results indicate that CYP4F2-mediated tocopherol-omega -hydroxylation is a central feature underlying the different biological half-lives, and therefore biopotencies, of the tocopherols and tocotrienols.


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