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Journal of Lipid Research, Vol. 48, 1090-1098, May 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Influence of major structural features of tocopherols and tocotrienols on their -oxidation by tocopherol--hydroxylase

Timothy J. Sontag and Robert S. Parker¹

Division of Nutritional Sciences, Cornell University, Ithaca, NY 14850

Published, JLR Papers in Press, February 6, 2007.

¹ To whom correspondence should be addressed. e-mail: rsp3{at}cornell.edu

Human cytochrome P450 4F2 (CYP4F2) catalyzes the initial -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 the number and positions 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 those of HepG2 cells. Although 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 V_max values than their tocopherol counterparts. Side chain stereochemistry had no effect on -hydroxylation of -tocopherol (-TOH) by any system. Kinetic analysis of microsomal CYP4F2 activity revealed Michaelis-Menten kinetics for -TOH but allosteric cooperativity for other vitamers, especially tocotrienols. Additionally, -TOH was a positive effector of -hydroxylation of other vitamers. These results indicate that CYP4F2-mediated tocopherol--hydroxylation is a central feature underlying the different biological half-lives, and therefore biopotencies, of the tocopherols and tocotrienols.

Supplementary key words vitamin E • cytochrome P450 • metabolism • kinetics • microsome • HepG2 • uptake • hydroxylation

Abbreviations: -CEHC, 2,7,8-trimethyl-2-(ß-carboxyethyl)-6-hydroxychroman; CYP4F2, cytochrome P450 4F2; -, -, and -T3, -, -, and -tocotrienol; - and -TOH, - and -tocopherol; -TTP, -tocopherol transfer protein

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