Human adults normally destroy about 200 billion erythrocytes per day. A 70-kg human therefore turns over approximately 6 g of hemoglobin daily. All products are reused. The globin is degraded to its constituent amino acids, and the released iron enters the iron pool. The iron-free porphyrin portion of heme is also degraded, mainly in the reticuloendothelial cells of the liver, spleen, and bone marrow.

The catabolism of heme from all heme proteins takes place in the microsomal fraction of cells by heme oxygenase, EC 1.14.18.18. Heme oxygenase synthesis is substrate-inducible, and heme also serves both as a substrate and as a cofactor for the reaction. The iron of the heme that reaches heme oxygenase has usually been oxidized to its ferric form (hemin). Conversion of one mole of heme- Fe³⁺ to biliverdin, carbon monoxide, and Fe³⁺ consumes three moles of O₂ , plus seven electrons provided by NADH and NADPH–cytochrome P450 reductase:

Fe³⁺-Heme + 3 O₂ + 7 e^– → biliverdin + CO + Fe³⁺

Despite its high affinity for heme- Fe²⁺, the carbon monoxide produced does not severely inhibit heme oxygenase. Birds and amphibians excrete the green-colored biliverdin directly. In humans, biliverdin reductase (EC 1.3.1.24) reduces the central methylene bridge of biliverdin to a methyl group, producing the yellow-pigmentbilirubin (Figure 1):

Biliverdin + NADPH + H⁺ → bilirubin + NADP⁺

Since 1 g of hemoglobin yields about 35 mg of bilirubin, human adults form 250 to 350 mg of bilirubin per day. This is derived principally from hemoglobin, and also from ineffective erythropoiesis and from catabolism of other heme proteins.

Fig1. Conversion of ferric heme to biliverdin, and then to bilirubin. (1) Conversion of ferric heme to biliverdin is catalyzed by the heme oxygenase system. (2) Subsequently, biliverdin reductase reduces bilirubin to bilirubin.

Conversion of heme to bilirubin by reticuloendothelial cells can be observed visually as the purple color of the heme in a hematoma slowly converts to the yellow pigment of bilirubin.

Bilirubin Is Transported to the Liver Bound to Serum Albumin

Bilirubin is only sparingly soluble in water. Consequently, it must be bound to serum albumin for transport to the liver. Albumin appears to have both high-affinity and low-affinity sites for bilirubin. The high-affinity site can bind approximately 25 mg of bilirubin/100 mL of plasma. More loosely bound bilirubin can readily be detached and diffused into tissues, and antibiotics and certain other drugs can compete with and displace bilirubin from albumin’s high-affinity site.

Further Metabolism of Bilirubin Occurs Primarily in the Liver

 Hepatic catabolism of bilirubin takes place in three stages: uptake by the liver, conjugation with glucuronic acid, and secretion in the bile.

Uptake of Bilirubin by Liver Parenchymal Cells

 Bilirubin is removed from albumin and taken up at the sinusoidal surface of hepatocytes by a large capacity, saturable facilitated transport system. Even under pathologic conditions, transport does not appear to be rate-limiting for the metabolism of bilirubin. The net uptake of bilirubin depends on its removal by subsequent metabolism. Once internalized, bilirubin binds to cytosolic proteins such as glutathione S-transferase, previously known as a ligandin, to prevent bilirubin from reentering the bloodstream.

Conjugation of Bilirubin With Glucuronate

Bilirubin is nonpolar, and would persist in cells (eg, bound to lipids) if not converted to a more water-soluble form. Bilirubin is converted to a more polar molecule by conjugation with glucuronic acid (Figure 2). A bilirubin-specific UDP-glucuronosyltransferase (EC 2.4.1.17) of the endoplasmic reticulum catalyzes stepwise transfer to bilirubin of two glucosyl moieties from UDP-glucuronate:

Bilirubin + UDP-glucuronate → bilirubin monoglucuronide + UDP

Bilirubin monoglucuronide + UDP-glucuronate → bilirubin diglucuronide + UDP

Fig2. Bilirubin diglucuronide. Glucuronate moieties are attached via ester bonds to the two propionate groups of bilirubin. Clinically, the diglucuronide is also termed “direct reacting” bilirubin.

Secretion of Bilirubin Into the Bile

Secretion of conjugated bilirubin into the bile occurs by an active transport mechanism, which probably is rate-limiting for the entire process of hepatic bilirubin metabolism. The protein involved is a multispecific organic anion trans porter (MOAT) located in the plasma membrane of the bile canaliculi. A member of the family of ATP-binding cassette transporters, MOAT transports a number of organic anions. The hepatic transport of conjugated bilirubin into the bile is inducible by the same drugs that can induce the conjugation of bilirubin. Conjugation and excretion of bilirubin thus constitute a coordinated functional unit.

Most of the bilirubin excreted in the bile of mammals is bilirubin diglucuronide. Bilirubin UDP-glucuronosyltransferase activity can be induced by several drugs, including phenobarbital. However, when bilirubin conjugates exist abnormally in human plasma (eg, in obstructive jaundice), they are pre dominantly monoglucuronides. Figure 3 summarizes the three major processes involved in the transfer of bilirubin from blood to bile. Sites that are affected in a number of conditions causing jaundice are also indicated.

Fig3. Diagrammatic representation of the three major processes (uptake, conjugation, and secretion) involved in the transfer of bilirubin from blood to bile. Certain proteins of hepatocytes bind intracellular bilirubin and may prevent its efflux into the bloodstream. The processes affected in certain conditions that cause jaundice are also shown.

Intestinal Bacteria Reduce Conjugated Bilirubin to Urobilinogen

 When conjugated bilirubin reaches the terminal ileum and the large intestine, the glucuronosyl moieties are removed by specific bacterial β-glucuronidases (EC 3.2.1.31). Subsequent reduction by the fecal flora forms a group of colorless tetra pyrroles called urobilinogens. Small portions of urobilinogens are reabsorbed in the terminal ileum and large intestine and subsequently are reexcreted via the enterohepatic urobilinogen cycle. Under abnormal conditions, particularly when excessive bile pigment is formed or when liver disease disrupts this intrahepatic cycle, urobilinogen may also be excreted in the urine. Most of the colorless urobilinogens formed in the colon are oxidized there to colored urobilins and excreted in the feces. Fecal darkening upon standing in air results from the oxidation of residual urobilinogens to urobilins.

Measurement of Bilirubin in Serum

 Quantitation of bilirubin employs a colorimetric method based on the reddish-purple color formed when bilirubin reacts with diazotized sulfanilic acid. An assay conducted in the absence of added methanol measures “direct bilirubin,” which is bilirubin glucuronide. An assay conducted in the presence of added methanol measures total bilirubin. The difference between total bilirubin and direct bilirubin is known as “indirect bilirubin,” and is unconjugated bilirubin.

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مواضيع ذات صلة

The Deoxyribonucleosides of Uracil & Cytosine are Salvaged

Biosynthesis of Pyrimidine Nucleotides

Hepatic Purine Biosynthesis is Stringently Regulated

Inosine Monophosphate (IMP) is Synthesized From Amphibolic Intermediates

DNA & RNA are Polynucleotides

Synthetic Nucleotide Analogs are Used in Chemotherapy

Chemistry of Purines, Pyrimidines, Nucleosides, & Nucleotides

Disorders of Bilirubin Metabolism

Disorders of Heme Biosynthesis

Porphyrins are Colored & Fluoresce

Heme is Synthesized From Succinyl-CoA & Glycine

NON–α-AMINO ACIDS