Bile Pigment

Bile Pigment

• Any of several colored compounds derived from porphyrin(myoglobin and heamoglobin) 
• Found in bile; principally bilirubin and biliverdin.
• Bilirubin is hydrophobic and potentially toxic compound.
• Bilirubin is metabolised like xenobiotics.
• I gm of Hemoglobin yields 35mg of bilirubin
•  Bilirubin has affinity for elastin, therefore jaundice is most easily seen in the sclera. 

SOURCE

• Iron –porphyrin (heme) group of heamoglobin is degraded, mainly in the reticuloendothelial cells of the liver, spleen, and bone marrow.
• Daily production is 4 mg/kg of bilirubin, deriving mainly (70-80%) from hemoglobin 
• But also from ineffective erythropoiesis and from various other heme proteins such as cytochrome and myoglobin.

 FORMATION

• In first step Heme oxygenase (HO 1) is an enzyme that catalyzes the degradation of heme. This produces biliverdin, iron, and carbon monoxide.
• In second step biliverdin is converted to bilirubin which is a tetrapyrrole, these conversion is catalyzed by biliverdin reductase.

TRANSPORTATION

•  Bilirubin is lipophilic and hydrophobic 
• i.e solubility in water is less
•  Hence circulating in plasma by covalently binding with albumin.
• Certain drugs as sulfonamides and salicylates compete with bilirubin for albumin binding 
• Displace bilirubin to enter into the brain in neonates and increase the risk of kernicterus
• A type of brain damage that can result from high levels of bilirubin in a baby’s blood. It can cause athetoid cerebral palsy and hearing loss

HEPATIC PHASE AND CONJUGATION                                                                                                               

• Bilirubin  is taken up across the sinusoidal membrane of hepatocytes by a carrier-mediated mechanism
•  Bound to ligandin.
• In liver unconjugated  bilirubin  is metabolized to bilirubin diglucuronide. 
• This conjugation process occur in endoplasmic reticulum UDP-glucuronosyl transferase.
• UDP-glucuronate (a product of uronic acid pathway) is  a donar of glucuronate residue for conjugation
• Conjugation increase the solubility of whole molecule hence making it polar,able to cross cell membrane, hydrophilic .
• Delete the toxicity of bilirubin(unconjugated bilirubin toxic to neuron).
• Stone formation is related to the deconjugation of bilirubin diglucuronide by bacterial beta glucuronidase.
• The process of conjugation can be induced by drugs phenobarbital.

EXCRETION OF BILIRUBIN INTO BILE

• Conjugated bilirubin is directed toward the canalicular membrane.
• Transported into the bile canaliculus by an adenosine triphosphate (ATP)-dependent pump.
• This energy-dependent, rate –limiting step is susceptible to impairment in liver disease.

FORMATION OF UROBILINS

• Conjugated bilirubin in plasma undergoes renal elimination .
• Bile is secreted into intestine where glucuronic acid is removed and the resulting bilirubin is converted to urobilinogen.
• A portion of urobilinogen is reabsorbed into blood, where it is converted to the yellow urobilin and excreted by kidneys.
• Urobilinogen is oxidized by intestinal bacteria to the brown Stercobilinogen which provide color to stool.
• Normal urine does not contain bilirubin. 
• Normal blood contains bilirubin in the uncongugated form which is not allowed to filter through the glomerulus. 
• Conjugated bilirubin is water soluble and filterable at the glomurulus, but not present in blood and hence does not filter to appear in the urine.

NORMAL RANGES

• Total bilirubin → 0.3 — 1.9 mg/dl
• Conjugated bilirubin → 0 to 0.3 mg/dl
• Unconjugated bilirubin → (0.3 — 1.6 mg/dl)

Exam Question

• Any of several colored compounds derived from porphyrin(myoglobin and heamoglobin)
• That are found in bile; principally bilirubin and biliverdin.
• Bilirubin is hydrophobic and potentially toxic compound.
• Daily production is 4 mg/kg of bilirubin,deriving mainly (70-80%) from hemoglobin 
• Also from ineffective erythropoiesis and from various other heme proteins such as cytochrome and myoglobin.
• Bilirubin is metabolised like xenobiotics.
• I gm of Hemoglobin yields 35mg of bilirubin
• Bilirubin has affinity for elastin, therefore jaundice is most easily seen in the sclera.
• Iron –porphyrin (heme) group of heamoglobin is degraded, mainly in the reticuloendothelial cells of the liver, spleen, and bone marrow.
• Bilirubin is lipophilic and hydrophobic i.e solubility in water is less hence circulating in plasma by covalently binding with albumin.
• Bilirubin  is taken up across the sinusoidal membrane of hepatocytes by a carrier-mediated mechanism
• Where it is bound to ligand
• In liver unconjugated  bilirubin  is metabolized to bilirubin diglucuronide  
• This conjugation process occur in endoplasmic reticulum UDP-glucuronosyl transferase.
• UDP-glucuronate (a product of uronic acid pathway) is  a donar of glucuronate residue for conjugation
• Conjugation increase the solubility of whole molecule hence making it polar,able to cross cell membrane
• Delete the toxicity of bilirubin(unconjugated bilirubin toxic to neuron).
• Stone formation is related to the deconjugation of bilirubin diglucuronide by bacterial beta glucuronidase.
• Conjugated bilirubin is directed toward the canalicular membrane, and it is transported into the bile canaliculus by an adenosine triphosphate (ATP)-dependent pum
• Conjugated bilirubin in plasma undergoes renal elimination .
• Urobilinogen is oxidized by intestinal bacteria to the brown Stercobilinogen which provide color to stool.
• Normal urine does not contain bilirubin because normal blood contains bilirubin in the uncongugated form which is not allowed to filter through the glomerulus
•  Conjugated bilirubin is water soluble and filterable at the glomurulus, but not presaent in blood normally and hence does not filter to appear in the urine.