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Vitamin E as a Potentiator of Vitamin K Inadequacy Public Deposited

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  • 2010 HHMI Symposium Presentation
  • The mechanisms by which vitamin E interferes with vitamin K activity, consequently decreasing blood clotting and increasing tendency to bleed, are currently unknown. The inactivity of vitamin in the body greatly affects γ-glutamyl carboxylase (GGCX), an enzyme requiring a vitamin K cofactor. As a result, the inactivity of GGCX, which allows substrates to bind calcium after γ-carboxylation, the efficiency of coagulation processes is decreased, ultimately due to the inactive concentrations of the enzyme’s vitamin K cofactor. Therefore, vitamin K is required for the posttranslational conversion of glutamyl to γ-carboxyglutamyl residues (Gla) in the precursors to several clotting factors synthesized in the liver, i.e., factors II (prothrombin), VII, IX and X, as well as precursor proteins synthesized in extrahepatic tissues, i.e., matrix Gla-protein (MGP) and osteocalcin (OC). The working hypothesis in discovering the mechanism by which vitamin E affects the activity of vitamin K is that elevated tissue α-tocopherol concentrations decrease the availability of vitamin K for vitamin K-dependent γ-glutamylcarboxylation, thereby resulting in under-γ-carboxylation of vitamin K dependant proteins. This hypothesis can be tested by determining alterations in Gla protein status in rats that have been supplemented in contrast to rat that have not been supplemented with α-tocopherol, the body’s preferred form of vitamin E. Serum concentrations of under-γ-carboxylated prothombrin (PIVKA-II) and under-γ-carboxylated OC effectively measure hepatic and extrahepatic vitamin K status. Hence, we troubleshot various methods of quantifying carboxylated and under-γ-carboxylated prothrombin and OC for measuring these levels in the plasma of rats, which have been fed experimental combinations of vitamin K1 or menadione, precursors to MK-4, with or without α-tocopherol injections. Despite the failure to effectively measure the activity of GGCX, which is dependent upon vitamin K availability, through OC ELISAs, other methods of quantifying the possible decrease of vitamin K availability, induced by vitamin E, were investigated. Various uptake and efflux transporters, like OATP and BCRP1 respectively, are responsible for the transport of lipid-soluble molecules. qRT-PCR was used to show a significant change in transcriptional levels of such transporters with excess vitamin E; therefore, it was hypothesized that up-regulation of the transporters could transport vitamin K metabolites too readily, thus excreting the active vitamin K before is can be utilized as a cofactor for vitamin K dependent proteins. In order to further support the previous transporter gene expression results determined via qRT-PCR, western blotting will be performed to quantify relative protein expression of said transporters.
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  • description.provenance : Submitted by Hannah Raines (rainesh@onid.orst.edu) on 2012-05-31T17:30:07Z No. of bitstreams: 1 Raines.pptx: 935424 bytes, checksum: 5557dcb97c34fe1e8813aae956607f11 (MD5)
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