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Formation and Elimination of Bilirubin
Haem is a planar; four heterocyclic nitrogen-containing rings (pyrrolic rings), containing many double bonds and an iron molecule at the center. Haem belongs to a group of molecules called porphyrins; haem is often referred to as porphyrin. So, in this sqadia lecture ´´Haem Catabolism´´ is pursued, starting with the Formation and Elimination of Bilirubin. When Hb is destroyed, protein portion globin is reutilized, or constituent amino acids are reutilized after proteolysis. Fe-free porphyrin portion of haem is degraded to bile pigments, Biliverdin and Bilirubin, in RE cells. The formation of Bilirubin, the chief bile pigment in humans, and its elimination from the body as a waste product of haem catabolism requires a series of metabolic alterations and transport processes. Partial or complete failure at any point in this sequence can result in clinical condition, Jaundice. Approximately 85 per cent of bilirubin is derived from senescent erythrocytes by conversion of ‘haem’ of Hb to biliverdin within RE cells. Oxidative scission of the iron-porphyrin ring takes place in presence of the enzyme haem α -Methenyl oxygenase, occurs in microsomal fractions of RE cells. The opening of the porphyrin ring in some way labels the removal of Fe. Whether the globin separated first or after ring opening, the bile pigment first formed is Biliverdin. Biliverdin is converted to bilirubin in RE cells. Fifteen per cent of newly synthesized bilirubin is derived from sources other than maturing circulating erythrocytes. Possible origins are destruction of immature erythrocytes in the bone marrow, degradation of hb, within erythrocyte precursors.
Transport of Bilirubin
The bilirubin formed in RE cells from breakdown of Hb is called “unconjugated bilirubin”, which is highly lipid soluble. Binding of bilirubin by albumin increases its solubility in plasma. Each molecule of albumin appears to have: one “high-affinity” site and one “low-affinity” site for bilirubin. The binding capacity of albumin for bilirubin can be modified by a variety of physical and chemical alterations. Administration of sulphonamides to pregnant women and neonates increases the risk of kernicterus in the jaundiced infants. Increased free fatty acids behave similarly. Liver appears to have a selective affinity to remove unconjugated bilirubin. Lateral extension of plasma membrane of liver cells facing hepatic sinusoids has specific receptor sites for bilirubin. Plasma membrane permeable to “non-polar molecules” like dissociated unconjugated bilirubin and an “intracellular” protein which act as an acceptor and facilitates the transfer of bilirubin to liver cells.
Bilirubin and D-glucuronic Acid Conjugation
Mammalian liver cells contain an enzyme referred to as glucuronyl transferase. The enzyme catalyzes the transfer of glucuronic acid from UDP-GA to various phenolic, carboxylic and amine receptors. The process is called conjugation reaction and it is carried out in the smooth endoplasmic reticulum of liver cells. Two glucuronyl groups are transferred from “active glucuronide” (UDPGA) by the catalytic action of glucuronyl transferase. In the conjugation reaction, monoglucuronide is formed first, followed by formation of bilirubin di-glucuronide. Mono and diglucuronides of bilirubin are called as conjugated bilirubins. Conjugated bilirubins are water soluble, smaller in molecular size as they are not bound to albumin. Recently glucuronyl transferase activity has also been detected in certain extrahepatic tissues, viz. skin, kidneys, adrenal glands, ovary, testes, intestinal mucosa and synovial membrane. Probably bilirubin monoglucuronide may be formed but not the diglucuronide in these tissues.
Secretion of Bilirubin in the Bile
Secretion of conjugated bilirubin into the bile occurs by an “active transport” mechanism. The protein involved is MRP-2 (multi drug resistance protein 2) also called “multispecific organic anion transporter” (MOAT). It is located in the plasma membrane of the bile canalicular membrane and handles a number of organic anions. Glucuronyl transferase activity may be inhibited by certain drugs, viz. novobiocin, dyes and steroidal derivatives, e.g. Pregnane –3 α -20 β -diol. The latter is an unusual isomer of pregnanediol which can form due to inherited defect in steroid metabolism. The isomer can inhibit the glucuronyl transferase activity and produce prolonged non-haemolytic unconjugated hyperbilirubinemia leading to jaundice in infants. Lucey-Driscoll Syndrome is a transient familial neonatal nonhemolytic unconjugated hyperbilirubinemia. Transient Neonatal “Physiological” Jaundice results from an accelerated haemolysis and due to an immature hepatic system for uptake, conjugation and secretion of bilirubin. Crigler-Najjar Syndrome Type I is a rare autosomal recessive disorder. Primary metabolic defect is inherited absence of glucuronyl transferase activity. Crigler-Najjar Syndrome Type II is a rare inherited disorder. It has milder defect in the bilirubin conjugating system and has a more benign course. Bile of these patients have been found to contain “bilirubin monoglucuronide” only. Gilbert’s Syndrome a heterogenous group of diseases, many of which are now recognised to be: due to a compensated haemolysis associated with unconjugated hyperbilirubinaemia, due to reduced glucuronyl transferase activity, and due to mutations in the gene encoding bilirubin UGT. Toxic Hyperbilirubinemia, Dubin-Johnson Syndrome, Rotor Syndrome, and Obstruction of the Biliary Tree are some more bilirubin related syndromes.
Excretion of Bile Pigments
Conjugated bilirubins are secreted in the GI tract in bile. In the lower portion of the intestinal tract, especially in the caecum and the colon, the bilirubin is released from the glucuronides with the help of the enzyme β-glucuronidase produced by bacteria, and then the released bilirubin is subjected to series of reductive action of enzyme systems present in the intestinal tract, mainly derived from the anaerobic bacteria in the caecum. Faecal flora as well as a pure strain of a Clostridium derived from the rat colon have been demonstrated in vitro to be able to complete the reduction of bilirubin to L-stercobilinogen. In the intestine, progressive hydrogenation occurs to produce a series of intermediary compounds. The various products derived from the progressive reduction of bilirubin may in part be absorbed from the intestine and returned to the liver for its re-excretion, called as enterohepatic circulation of bile pigments.