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]