Tetrapyrroles icterus

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					         Tetrapyrroles
     Metabolism of porphyrins
               Eva Samcová




                  Heme                            Amino acids like precursors of
                                                  Porphyrins
Hemoglobin                                        Neurotransmitters
Myoglobin                                         Hormones
Cytochrome c                                      Purines and pyrimidines
Catalase (enzymes can oxidize substrates
with H2O2 as the oxidant – peroxidase reaction)
Chlorophyll with Mg
Vitamin B12 or cobalamine with corrin ring
systém resembling to heme with Co2+
          Porphyrins                         Structure of porphyrins
Cyklic compounds binding metal ions   ● 4 pyrrole nuclei linked in a planar ring by
mostly Fe2+ and Fe3+                    four α-methylene bridges
Heme –the most frequent               ● Porphyrins are different in side chains of
metalloporphyrin                        pyrroles nuclei
Heme as prosthetic group of           ● Heme´s extensive network of conjugated
hemoglobin, myoglobin, cytochrome,     double bonds absorbs light at the low end
catalase                               of the visible spectrum
Heme proteins are synthesized and
degraded very fast (6-7g per day)




         Structure of heme                           Heme Biosynthesis
                                        Where is synthesis realized : bone marrow
                                        85%, much smaller in liver, but can be
                                        produced in virtually all mammalian tissues
                                        In cell : mitochondria and cytosol
                                        (cytoplasm)
                                        Succinyl-CoA condenses with glycine to yield an
                                        intermediate that is then decarboxylated to give
                                        δ-aminolevulinate, enzym ALA-synthase,
                                        key regulatory enzym
                                        Formation of porphobilinogen
                                        (dehydratation), acute lead poisoning
                                        Formation of uroporphyrinogen III
                                        Formation of heme
                                  Heme
                                  Biosynthesis




From porphobilinogen to coproporphyringen III    Protoporphyrinogen IX
    Change of protoporohyrinogenu IX to
            protoporphyrin IX                           Porphyrias
                                          A whole series of hereditary or acquired
                                          diseases (porphyrias) are associated with
                                          disturbances in porphyrin biosynthesis
                                          Several of these disorders result in the
                                          excretion of heme precursors in the stool
                                          or urine giving them a dark red colour.
                                          Porphyrins may also accumulate in the
                                          skin (light-shynes, poorly-healing blisters)
                                          Neurological disturbances are also
                                          common




   Medieval legend Dracula
                                                                     Degradation of heme
It is possible that medieval legend                                  100-200 million
describing human vampires had their                                  erythrocytes/per hour

origin in the behavior of porphyria                                  The start of
                                                                     degradation in ER
sufferers (lighht-shyness, bizarre                                   RES (liver, spleen and
appearance, drinking of blood to                                     bone marrow)
compensate for the heme deficiency)
                                                     Degradation of heme (2.)
          Degradace hemu




                                          Determination of bilirubin in the serum is of
Biosynthesis of bilirubin diglucuronide
                                                          great value
                                          Devised by Van den Bergh by application
                                          of Ehrlich´s test for bilirubin in urine
                                          Ehrlich´s test is based on the coupling of
                                          diazotized sulfanilic acid (Ehrlich´s diazo
                                          reagent) and bilirubin, to produce a
                                          reddish purple azo compound.
                                          To measure after addition of methanol,
                                          indirect bilirubin = unconjugated b.
                                          To measure without methanol direct
                                          bilirubin = conjugated bilirubin
      Hyperbilirubinemia result from in
                                                                     Hyperbilirubinemia
            consequence of :

  Increased formation of bilirubin                        When bilirubin in the blood exceeds 1
  Decreased ability of liver parenchym to                 mg/L (17.1 mol/L), hyperbilirubinemia
  trapp the bilirubin                                     exists – more bilirubin than the healthy
                                                          liver can excrete – bilirubin accumulates in
  Lower ability of liver to conjugate bilirubin
                                                          the blood. Then bilirubin diffuses into the
  Disturbance of bilirubin excretion into the             tissues, which then become yellow →
  bile                                                    Jaundice or Icterus
  Disturbance of bile outflow




                       Jaundice                               Icterus and hemolytic anemia
Jaundice can be caused :
                                                          Icterus is symptom of diseases
1. Excessive formation of bilirubin by increased
                                                          which can have different etiology.
  degradation of erythrocytes -hemolytic anemia           Hemolytic anemia:is important cause
   hereditary enzyme defects or poisoning                 of unconjugated hyperbilirubinemia
2. Impaired excretion as a result of hereditary or        Neonatal „Physiological Jaundice“ , it
  acquired liver defects – hepatocellular anemia
                                                          results from an accelarated hemolysis and
3. Impaired excretion of gall– obstructive
  jaundice due to gallstones
                                                          an immature hepatic system for the
                                                          uptake, conjugation and secretion of
  Unconjugated bilirubin can even cross the blood-brain   bilirubin
  barrier leading to brain damage (Kernicterus)
  Only conjugated bilirubin, you can find in urine
        Icterus hepatocellular                              Icterus hepatocellular

Injury to the liver by
                                                 Gilbert´s disease – defect in the hepatic clearance of
inflammation(hepatitis), cirrhosis or        -
                                                 bilirubin, possibly due to a defect in the uptake of
by toxic effects                                 bilirubin by the liver parenchymal cells
Primary metabolic defect in conjugation of
                                              - Toxic hyperbilirubinemia –
bilirubin – inherited absence of bilirubin      can result from toxin-induced liver dysfunction
UDP-glucuronosyltransferase activity in         (chloroform, tetrachloromethane, acetaminophen,
                                                hepatitis virus, cirrhosis, toadstools poisoning ,
hepatic tissue - Grigler-Najjar syndrom I       disturbance of liver parenchyma cells
                                             ●




         Obstructive jaundice
Conjugated hyperbilirubinemia commonly
results from blockage of the hepatic or
common bile ducts – conjugated
bilirubin in blood
Because of the obstruction, bilirubin               Do not forget to study the following
diglucuronide cannot be excreted. It thus
regurgitates into hepatic veins and                               themes
lymphatics, and conjugated bilirubin
appears in the blood and urine

(Urobillinogen in urine and absence of
bilirubin on the other side gives evidence
about unconjugated hyperbilirubinemia in
case of hemolytic icterus)
                            Hemoglobin
                            Allosteric effects
                            Bohr effect




Metabolism of erytrocytes
Glycolysis
Pentose phosphate pathway

				
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posted:1/27/2011
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