Introduction:
Bile pigments are colored compounds formed during the breakdown of hemoglobin from aged red blood cells. They are excreted through bile and consist mainly of two pigments:
- Bilirubin – an orange-yellow pigment
- Biliverdin – a green pigment (oxidized form of bilirubin)
Red blood cells (RBCs) have an average lifespan of 120 days. After this period, they are destroyed by macrophages of the reticuloendothelial (RE) system in the spleen and liver. During this process, hemoglobin is split into two parts: the protein portion globin and the non-protein portion heme.
In adults (around 70 kg), about 6 grams of hemoglobin are broken down and resynthesized each day.
Fate of Globin
The globin portion of hemoglobin can be reused for new hemoglobin formation or broken down into individual amino acids. These amino acids then enter general amino acid metabolism or are used again to synthesize fresh globin chains.
Sources of Heme for Degradation
Approximately 80% of the heme that undergoes degradation comes from mature RBCs, while the remaining 20% originates from immature red blood cells, myoglobin, and cytochromes.
Step 1: Conversion of Heme to Biliverdin
The first step in bile pigment production involves the enzyme heme oxygenase, a complex microsomal enzyme located in macrophages. This enzyme uses NADPH and oxygen (O₂) to cleave the methenyl bridge between two pyrrole rings (A and B) of the heme molecule.
The reaction produces:
- Biliverdin – a green pigment
- Ferric iron (Fe³⁺) – released from the heme structure
- Carbon monoxide (CO) – formed during the cleavage
In birds and amphibians, biliverdin is excreted directly. In mammals, however, biliverdin is further reduced to form bilirubin.
Step 2: Conversion of Biliverdin to Bilirubin
The enzyme biliverdin reductase catalyzes the reduction of biliverdin to bilirubin using NADPH as a coenzyme. This reduction occurs at the methenyl bridge between the pyrrole rings C and D.
Bilirubin is a yellow pigment that represents the main bile pigment in humans. On average, 1 gram of hemoglobin breakdown yields about 35 mg of bilirubin. In adults, approximately 250–350 mg of bilirubin is produced daily.
The term bile pigments collectively refers to bilirubin and its related derivatives.
Transport of Bilirubin to the Liver
Bilirubin is lipophilic and insoluble in water. Therefore, in the bloodstream, it is transported in a bound form attached non-covalently to albumin. Each albumin molecule has two types of binding sites for bilirubin:
- High-affinity site: Holds bilirubin tightly (about 25 mg per 100 ml of plasma).
- Low-affinity site: Binds bilirubin loosely, allowing easier release into tissues.
Certain drugs (e.g., sulfonamides, salicylates) can displace bilirubin from albumin. When this occurs, bilirubin may enter the brain and cause neuronal damage — especially dangerous in newborns, leading to kernicterus.
Once the albumin-bilirubin complex reaches the liver, bilirubin is actively taken up by hepatocytes (liver cells) via carrier-mediated transport. Inside these cells, bilirubin binds to an intracellular protein called ligandin, which helps maintain it in soluble form until further metabolism.
Conjugation of Bilirubin in the Liver
Within the liver, bilirubin undergoes conjugation to increase its water solubility. It reacts with two molecules of glucuronic acid derived from UDP-glucuronate. This reaction is catalyzed by the enzyme bilirubin glucuronyltransferase located in the smooth endoplasmic reticulum.
This process produces bilirubin diglucuronide (a water-soluble form). When bilirubin levels are high, some bilirubin monoglucuronide may also accumulate. The enzyme bilirubin glucuronyltransferase can be stimulated by certain drugs such as phenobarbital, which helps enhance bilirubin metabolism.
Excretion of Bilirubin into Bile
The conjugated bilirubin is actively transported from hepatocytes into bile canaliculi and then into bile. This movement occurs against a concentration gradient and requires energy (active transport).
This is the rate-limiting step of bilirubin metabolism and can be easily impaired in liver disease. Normally, more than 98% of bilirubin excreted into bile is in the conjugated form.
Fate of Bilirubin in the Intestine
Once bilirubin reaches the intestine through bile, it is acted upon by bacterial enzymes known as β-glucuronidases, which hydrolyze bilirubin glucuronides to release free bilirubin. This bilirubin is then converted by intestinal bacteria into urobilinogen, a colorless compound.
Part of this urobilinogen is reabsorbed into the bloodstream and undergoes two fates:
- Converted to urobilin in the kidneys and excreted in urine, giving urine its characteristic yellow color.
- Converted by intestinal bacteria into stercobilin, which is excreted in feces and gives stool its brown color.
Detailed Notes:
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