Enterohepatic circulaton

Enterohepatic circulation refers to the recycling process of certain substances between the liver and the intestines. This process is critical for the metabolism and recirculation of bile acids, bilirubin, drugs, and other substances. 

Overview

1. Secretion: Substances are secreted by the liver into the bile.
2. Storage and Release: Bile is stored in the gallbladder and released into the small intestine.
3. Reabsorption: Substances are reabsorbed in the intestines and transported back to the liver via the portal vein.
4. Re-excretion: The liver reprocesses these substances and secretes them back into the bile.

Key Components

1. Bile Acids: Synthesized from cholesterol in the liver, they aid in the digestion and absorption of dietary fats.
2. Bilirubin: A breakdown product of hemoglobin, excreted in bile.
3. Drugs and Metabolites: Many drugs undergo enterohepatic recycling, affecting their pharmacokinetics and duration of action.

Examples

1. Bile Acids:

   • Primary Bile Acids: Cholic acid and chenodeoxycholic acid are synthesized in the liver from cholesterol.
   • Secondary Bile Acids: Deoxycholic acid and lithocholic acid are formed in the intestine by bacterial action on primary bile acids.

2. Bilirubin:

   • Formed from the breakdown of hemoglobin in the spleen, transported to the liver, conjugated to glucuronic acid, and secreted into bile.

3. Drugs:

   • Ezetimibe: A cholesterol-lowering drug that undergoes enterohepatic circulation, contributing to its prolonged effect.
   • Mycophenolic Acid: An immunosuppressant that undergoes glucuronidation in the liver and is reabsorbed in the intestine.

Chemical Reactions

1. Formation of Bile Acids:

   • Cholesterol is converted to cholic acid and chenodeoxycholic acid in the liver via a series of enzymatic reactions involving hydroxylation and side-chain oxidation.
   $$\text{<span style="font-size: small;"><span style="font-family: arial;">Cholesterol</span></span>}\stackrel{\text{<span style="font-size: small;"><span style="font-family: arial;">Hydroxylation</span></span>}}{<span\; style="font-size:\; small;"><span\; style="font-family:\; arial;">\to </span></span>}\text{<span style="font-size: small;"><span style="font-family: arial;">7α-Hydroxycholesterol</span></span>}\stackrel{\text{<span style="font-size: small;"><span style="font-family: arial;">Oxidation</span></span>}}{<span\; style="font-size:\; small;"><span\; style="font-family:\; arial;">\to </span></span>}\text{<span style="font-size: small;"><span style="font-family: arial;">Cholic Acid</span></span>}$$

2. Conjugation of Bilirubin:

   • Bilirubin is conjugated with glucuronic acid in the liver to form bilirubin diglucuronide, which is more water-soluble.
   $$\text{<span style="font-size: small;"><span style="font-family: arial;">Bilirubin</span></span>}<span\; style="font-size:\; small;"><span\; style="font-family:\; arial;">+</span></span>\mathrm{<span\; style="font-size:\; small;"><span\; style="font-family:\; arial;">2</span></span>}\text{<span style="font-size: small;"><span style="font-family: arial;">UDP-Glucuronic Acid</span></span>}\stackrel{\text{<span style="font-size: small;"><span style="font-family: arial;">UDP-Glucuronyltransferase</span></span>}}{<span\; style="font-size:\; small;"><span\; style="font-family:\; arial;">\to </span></span>}\text{<span style="font-size: small;"><span style="font-family: arial;">Bilirubin Diglucuronide</span></span>}<span\; style="font-size:\; small;"><span\; style="font-family:\; arial;">+</span></span>\mathrm{<span\; style="font-size:\; small;"><span\; style="font-family:\; arial;">2</span></span>}\text{<span style="font-size: small;"><span style="font-family: arial;">UDP</span></span>}$$

3. Drug Metabolism and Reabsorption:

   • Mycophenolic acid is converted to its glucuronide form in the liver and then reabsorbed in the intestine after deconjugation by intestinal bacteria.
   $$\text{<span style="font-size: small;"><span style="font-family: arial;">Mycophenolic Acid</span></span>}<span\; style="font-size:\; small;"><span\; style="font-family:\; arial;">+</span></span>\text{<span style="font-size: small;"><span style="font-family: arial;">UDP-Glucuronic Acid</span></span>}\stackrel{\text{<span style="font-size: small;"><span style="font-family: arial;">UDP-Glucuronyltransferase</span></span>}}{<span\; style="font-size:\; small;"><span\; style="font-family:\; arial;">\to </span></span>}\text{<span style="font-size: small;"><span style="font-family: arial;">Mycophenolic Acid Glucuronide</span></span>}<span\; style="font-size:\; small;"><span\; style="font-family:\; arial;">+</span></span>\text{<span style="font-size: small;"><span style="font-family: arial;">UDP</span></span>}$$

Physiological Significance

1. Efficiency: Enhances the body's efficiency in using bile acids and other substances, reducing the need for constant synthesis.
2. Drug Effect: Influences the pharmacokinetics and duration of action of certain drugs.
3. Homeostasis: Maintains the balance of critical compounds like cholesterol and bilirubin.

Clinical Implications

1. Interference by Drugs: Antibiotics that alter gut flora can disrupt enterohepatic circulation by reducing bacterial deconjugation of bile acids.
2. Diseases: Liver diseases can impair enterohepatic circulation, leading to conditions like jaundice due to the accumulation of bilirubin.
3. Drug Interactions: Drugs undergoing enterohepatic recycling can have prolonged half-lives, leading to potential drug interactions and toxicity.

In summary, enterohepatic circulation is a crucial physiological process that recycles bile acids, bilirubin, and certain drugs, significantly impacting their metabolism, effectiveness, and homeostasis.