Heme is an iron-containing molecule and a component of hemoglobin, the protein responsible for oxygen transport within red blood cells. Although necessary for respiration, free heme is potentially toxic because it can catalyze the formation of damaging free radicals. Heme degradation is a necessary biological mechanism for disposing of this toxic byproduct. This pathway neutralizes heme’s toxicity and prepares its components for either recycling or safe excretion as waste.
The Source of Heme Requiring Degradation
Most heme requiring degradation comes from the natural turnover of aged red blood cells. These senescent cells are primarily recognized and engulfed by specialized immune cells called macrophages, mainly located in the spleen, liver, and bone marrow. Once a macrophage engulfs an old red blood cell, the hemoglobin is separated into globin protein chains and the heme group. The globin chains are broken down into amino acids and recycled for new protein synthesis. The heme component, which contains the toxic protoporphyrin ring, must be systematically broken down and eliminated.
The Initial Enzymatic Transformation
The chemical breakdown of the heme molecule begins inside the macrophage and requires two sequential enzymatic steps. The first step is catalyzed by heme oxygenase (HO), which opens the porphyrin ring through an oxidation reaction. This process forms the green pigment biliverdin, releases the central iron atom (\(\text{Fe}^{2+}\)) for reuse, and generates carbon monoxide (CO).
Biliverdin reductase (BVR) then converts biliverdin into unconjugated bilirubin, a yellow pigment, using reducing power supplied by NADPH. This unconjugated form is highly nonpolar and lipid-soluble. Since unconjugated bilirubin is toxic and water-insoluble, it cannot travel freely through the bloodstream or be excreted directly by the kidneys.
Hepatic Processing and Excretion of Bilirubin
After formation, unconjugated bilirubin is released into the bloodstream and must be bound to a carrier protein for transport. The plasma protein albumin serves as the primary transport vehicle, binding to bilirubin to carry it through the circulation to the liver. Upon reaching the liver, the unconjugated bilirubin is taken up by liver cells (hepatocytes), where detoxification continues.
Inside the hepatocyte, the enzyme Uridine Diphosphoglucuronosyltransferase (UGT) performs conjugation. This process attaches glucuronic acid molecules to the bilirubin, converting it into water-soluble conjugated bilirubin. This non-toxic form is actively secreted by the liver into the bile ducts as a component of bile, which is then released into the small intestine.
In the small intestine and colon, gut bacteria deconjugate the bilirubin and metabolize it into colorless urobilinogens. Most urobilinogen is converted into stercobilin, the compound responsible for giving feces its brown color. A small fraction is reabsorbed into the bloodstream, travels to the kidneys, and is converted into urobilin and excreted, providing the yellow color to urine.
Clinical Indicators of Impaired Degradation
The buildup of bilirubin in the bloodstream (hyperbilirubinemia) indicates that the degradation pathway is impaired or overwhelmed. When serum bilirubin levels exceed a threshold, the pigment deposits in tissues, causing the visible yellow discoloration of the skin and eyes, known as jaundice. Jaundice can result from excessive bilirubin production, such as rapid red blood cell destruction, or from the liver’s failure to conjugate or excrete it.
Changes in the color of bodily waste products also provide clues about the problem’s location. If the flow of conjugated bilirubin to the intestine is blocked, feces become pale or clay-colored due to the absence of stercobilin. This blockage also forces conjugated bilirubin to accumulate in the blood and spill into the urine, causing the urine to appear abnormally dark. Conversely, overproduction of unconjugated bilirubin can lead to elevated urinary urobilinogen, resulting in darker yellow urine.