How is aldosterone metabolized by the liver?

Aldosterone Metabolism in the Liver

Aldosterone is primarily metabolized in the liver through reduction and conjugation with glucuronic acid, with the main hepatic metabolite being 3α,5β-tetrahydroaldosterone-3-glucuronide, which is then excreted in bile and urine 1.

Primary Metabolic Pathways

The liver metabolizes aldosterone predominantly through reduction reactions followed by glucuronidation, producing tetrahydroaldosterone as the most abundant metabolite, which is then conjugated for excretion.

The metabolic process involves several steps:

1. Reduction reactions: Aldosterone undergoes reduction in the A-ring of its steroid structure

   • 5α-reduced and 5β-reduced metabolites are formed, with 5α-reduced metabolites showing higher mineralocorticoid activity 2
   • 3α-reduced metabolites are more potent than 3β-reduced metabolites 2

2. Glucuronidation: The reduced metabolites are conjugated with glucuronic acid

   • This process is primarily catalyzed by UDP-glucuronosyltransferase-2B7 (UGT2B7) in the liver 3
   • UGT1A10 also contributes to aldosterone glucuronidation, though to a lesser extent 3

3. Excretion: The conjugated metabolites are excreted in bile and ultimately in urine

Enzymatic Control and Kinetics

Hepatic aldosterone metabolism exhibits Michaelis-Menten kinetics with the following parameters:

• Mean Km: 509 ± 137 μM
• Mean Vmax: 1075 ± 429 pmol min⁻¹ mg⁻¹
• Mean CLint: 2.36 ± 1.12 μl min⁻¹ mg⁻¹ 3

Factors Affecting Aldosterone Metabolism

Several factors can influence the hepatic metabolism of aldosterone:

1. Glucocorticoid levels:

   • Glucocorticoid excess reduces hepatic clearance of aldosterone by approximately 19% 4
   • This affects the ratio between circulating polar metabolites and less polar metabolites 4

2. Medication interactions:

   • NSAIDs compete for UGT2B7, inhibiting aldosterone glucuronidation 3
   • The inhibition potency follows: fenamates > diclofenac > arylpropionates 3
   • This interaction may contribute to NSAID-induced adverse renal effects and hypertension 3

3. Liver disease:

   • In cirrhosis, impaired aldosterone metabolism contributes to secondary hyperaldosteronism 5
   • This leads to increased sodium and water reabsorption in the distal renal tubule 5
   • Spironolactone, an aldosterone antagonist, is used to counteract this effect in cirrhotic patients with ascites 5

Clinical Significance

The metabolism of aldosterone has important clinical implications:

• In liver cirrhosis, reduced aldosterone clearance contributes to ascites formation through sodium and water retention 5
• Measurement of aldosterone metabolites, particularly tetrahydroaldosterone, can be used in the diagnosis of primary aldosteronism 1
• Drug interactions affecting aldosterone metabolism (particularly NSAIDs) may contribute to hypertension and fluid retention 3

Comparative Metabolism

While the liver is the primary site of aldosterone metabolism, the kidney also metabolizes aldosterone:

• The main renal metabolite is aldosterone-18-oxo-glucuronide 1
• Renal metabolism exhibits similar kinetic parameters but with slightly higher clearance (CLint: 3.91 ± 2.35 μl min⁻¹ mg⁻¹) 3

Understanding aldosterone metabolism is crucial for managing conditions like primary aldosteronism, cirrhosis with ascites, and drug interactions that may affect blood pressure regulation and fluid balance.