Influence of major structural features of tocopherols and tocotrienols on their ω-oxidation by tocopherol-ω-hydroxylase
Human cytochrome P450 4F2 (CYP4F2) catalyzes the initial ω-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 inf...
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| Format: | Article |
| Language: | English |
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Elsevier
2007-05-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520435552 |
| _version_ | 1818640067898376192 |
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| author | Timothy J. Sontag Robert S. Parker |
| author_facet | Timothy J. Sontag Robert S. Parker |
| author_sort | Timothy J. Sontag |
| collection | DOAJ |
| description | Human cytochrome P450 4F2 (CYP4F2) catalyzes the initial ω-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 Vmax values than their tocopherol counterparts. Side chain stereochemistry had no effect on ω-hydroxylation of α-tocopherol (α-TOH) by any system. Kinetic analysis of microsomal CYP4F2 activity revealed Michaelis-Menten kinetics for α-TOH but allosteric cooperativity for other vitamers, especially tocotrienols. Additionally, α-TOH was a positive effector of ω-hydroxylation of other vitamers. These results indicate that CYP4F2-mediated tocopherol-ω-hydroxylation is a central feature underlying the different biological half-lives, and therefore biopotencies, of the tocopherols and tocotrienols. |
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| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-16T23:05:23Z |
| publishDate | 2007-05-01 |
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| series | Journal of Lipid Research |
| spelling | doaj.art-a41b567fec5c474b89a7461d54945e812022-12-21T22:12:35ZengElsevierJournal of Lipid Research0022-22752007-05-0148510901098Influence of major structural features of tocopherols and tocotrienols on their ω-oxidation by tocopherol-ω-hydroxylaseTimothy J. Sontag0Robert S. Parker1Division of Nutritional Sciences, Cornell University, Ithaca, NY 14850Division of Nutritional Sciences, Cornell University, Ithaca, NY 14850Human cytochrome P450 4F2 (CYP4F2) catalyzes the initial ω-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 Vmax values than their tocopherol counterparts. Side chain stereochemistry had no effect on ω-hydroxylation of α-tocopherol (α-TOH) by any system. Kinetic analysis of microsomal CYP4F2 activity revealed Michaelis-Menten kinetics for α-TOH but allosteric cooperativity for other vitamers, especially tocotrienols. Additionally, α-TOH was a positive effector of ω-hydroxylation of other vitamers. These results indicate that CYP4F2-mediated tocopherol-ω-hydroxylation is a central feature underlying the different biological half-lives, and therefore biopotencies, of the tocopherols and tocotrienols.http://www.sciencedirect.com/science/article/pii/S0022227520435552vitamin Ecytochrome P450metabolismkineticsmicrosomeHepG2 |
| spellingShingle | Timothy J. Sontag Robert S. Parker Influence of major structural features of tocopherols and tocotrienols on their ω-oxidation by tocopherol-ω-hydroxylase Journal of Lipid Research vitamin E cytochrome P450 metabolism kinetics microsome HepG2 |
| title | Influence of major structural features of tocopherols and tocotrienols on their ω-oxidation by tocopherol-ω-hydroxylase |
| title_full | Influence of major structural features of tocopherols and tocotrienols on their ω-oxidation by tocopherol-ω-hydroxylase |
| title_fullStr | Influence of major structural features of tocopherols and tocotrienols on their ω-oxidation by tocopherol-ω-hydroxylase |
| title_full_unstemmed | Influence of major structural features of tocopherols and tocotrienols on their ω-oxidation by tocopherol-ω-hydroxylase |
| title_short | Influence of major structural features of tocopherols and tocotrienols on their ω-oxidation by tocopherol-ω-hydroxylase |
| title_sort | influence of major structural features of tocopherols and tocotrienols on their ω oxidation by tocopherol ω hydroxylase |
| topic | vitamin E cytochrome P450 metabolism kinetics microsome HepG2 |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520435552 |
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