MUDr. Dana Maňasková


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Degradace a metabolismus vitamínu E

Degradace oxidací

  • Reakce s dalším peroxylovým radikálem za vzniku stabilního produktu
    • Alfa-tokoferol
      • Alfa-tokoferylquinon
        • Metabolizován a vyloučen močí
  • Alpha-CEHC is formed directly from alpha-tocopherol
    • By side-chain oxidation
    • Eliminated in the urine (Schultz et al., 1995)
    • 4.26 ± 1.38 % of the radioactive dose was eliminated via urine (Chuang et al., 2011)
  • Novotny et al. (2012)
    • Mean daily total urine losses of alpha-tocopherol
      • Cca 0.85 mg/day [2]

Vitamín C

  • Double-blind, placebo-controlled trial in 11 smokers and 13 nonsmokers
  • Given alpha-tocopherol and gamma-tocopherol labeled with deuterium (hence traceable)
  • Supplementation with vitamin C
    • Reduced the rate of vitamin E loss in plasma
      • Most probably by regenerating tocopheryl radicals back to nonoxidized forms [10]

Jaterní degradace

Hepatic omega-hydroxylase - Human cytochrome P450 4F2 (CYP4F2)

  • In human liver microsomes [9]
  • Play critical roles in controlling the metabolism of alpha-tocopherol [2]
    • CYP4F2 is the only enzyme currently shown to metabolize vitamin E in humans [9]
  • Cytochromes CYP34A and CYP4F2
    • Isoforms that are involved in the oxidation of alpha-tocopherol and gamma-tocopherol [8]
    • Highly polymorphic in the context of proteins that are important in VE homeostasis
  • Omega-hydroxylation of the terminal methyl group of the phytyl side chain of vitamin E
    • Form the 13'-OH product [9]
  • CYP4F2 is part of an endoplasmic reticulum membrane-bound complex requires
    • The cytochrome P450 (CYP) enzyme itself
    • Reducing equivalents from NADPH via the electron donor cytochrome P450 reductase [9]
  • Wild-type CYP4F2 activity toward a wide variety of naturally occurring and synthetic vitamin E substrates
    • T3 were in general metabolized more readily than the TOH [9]

Hydroxylation of:

  • Leukotriene-B4
  • Arachidonic acid [8]
    • Shares its activity toward AA and leukotriene B4 with several other P450 enzymes [9]
  • Alpha-Tocopherol not bound to alpha-TTP
    • To 2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman (alpha-CEHC) (Schultz et al., 1995) [5]
    • Catabolized to counteract excess VE when the capacity of liver alpha-TTP is exceeded [8]
    • Activity towards alpha-tocopherol is lower than towards other tocopherols (Sontag and Parker, 2007)
  • Tocopherols (TOH) and tocotrienols (T3)
    • Omega-hydroxylation of the side chain
    • The first step in their catabolism to polar metabolites excreted in urine
  • Low affinity forms of VE for alpha-TTP, such as gamma-tocopherol
    • Conversion to CEHC in hepatocytes
    • Eliminated in the urine after
      • Faster than with alpha-tocopherol forms
    • Excreted via bile acids
    • CYP4F2 has stronger activity towards tocopherols other than alpha-tocopherol - various naturally occurring forms of vitamin E
      • Forms with incomplete methylation of the phenol ring or with unsaturated side chains are metabolized more rapidly [9]
      • Alpha-tocopherol predominantly accumulates in body tissues
      • Other tocopherols are preferentially catabolised in the liver [2]

Inhibice CYP4F2

  • In mice, depletion
    • Causes gamma-tocopherol accumulation in plasma and tissues
    • Reduction in the excretion of -oxidation metabolites [8]
  • Dietary sesamin
    • A sesame seed lignan
    • Inhibitor of CYP4F2
    • Resulted in elevated concentrations of alpha- and gamma-TOH in rat serum [9]
    • Short-term administration of moderate amounts of sesame seeds to humans resulted in elevations in serum gamma-TOH levels [9]

Beta-oxidation

  • May occur both in peroxisomes and mitochondria
    • But mitochondria were the only site for alpha-CEHC production in rat liver homogenates (Mustacich et al., 2010)
  • Truncation of the molecule into short chain

Conjugation

  • Glucuronide conjugates of alpha-CEHC in plasma and in urine of
    • CEHC
    • CEHC sulfate
    • CEHC glycoside (Pope et al., 2002; Cho et al., 2009; Johnson et al., 2012)
    • Alpha-CEHC glycine
    • Alpha-CEHC glycine glucuronide
    • Alpha-CEHC taurine (Johnson et al., 2012) [2]

Excretion

  • Different metabolites from tocopherols and tocotrienols have been identified (Zhao et al., 2010) [2]
  • More water-soluble carboxychromanol metabolites that are excreted in urine [9]



Metabolismus VE v GIT

  • Tocopherol esters are hydrolysed in the duodenum by pancreatic hydrolases
  • Bioavailability of the free and ester forms is similar (Cheeseman et al., 1995) [2]


O úroveň výše

Poslední aktualizace: 21. 2. 2020 0:41:01