Heme degradation

Category: catabolism

Overview

Senescent RBCs phagocytosed by reticuloendothelial macrophages → heme oxygenase (HO-1 inducible + HO-2 constitutive) cleaves heme → biliverdin + CO (free!) + Fe2+ (recycled via transferrin). Biliverdin reductase → unconjugated bilirubin (lipid-soluble, albumin-bound). Hepatic uptake → UGT1A1 conjugation with glucuronic acid → conjugated bilirubin (water-soluble; biliary excretion). Intestinal bacteria deconjugate + reduce to urobilinogen → ~80% excreted as stercobilin (fecal color); ~20% absorbed + recycled / renally excreted as urobilinogen (urine color). Clinical: Gilbert syndrome = UGT1A1 promoter polymorphism → mild unconjugated hyperbilirubinemia (~5% population; benign; can present with fasting/stress jaundice); Crigler-Najjar = severe UGT1A1 deficiency (autosomal recessive). Atazanavir + indinavir inhibit UGT1A1 → unconjugated hyperbilirubinemia + scleral icterus (benign).

Organ Systems

Pathway Steps

  1. heme → biliverdin — via heme oxygenase (HO-1 + HO-2); releases CO + Fe2+. Heme oxygenase (inducible HO-1, constitutive HO-2) opens the porphyrin ring, releasing carbon monoxide (the main endogenous CO source, a gasotransmitter) and Fe²⁺ for recycling. HO-1 is a key Nrf2-induced cytoprotective/antioxidant stress enzyme.
  2. biliverdin → unconjugated-bilirubin — via biliverdin reductase. Biliverdin reductase yields unconjugated (indirect) bilirubin — lipophilic, albumin-bound in blood, and itself a potent antioxidant. Being lipid-soluble it can cross the blood–brain barrier, the basis of neonatal kernicterus risk.
  3. unconjugated-bilirubin → conjugated-bilirubin — via UGT1A1 — GILBERT / CRIGLER-NAJJAR enzyme; ATAZANAVIR-INHIBITED. UGT1A1 glucuronidates bilirubin to the water-soluble conjugated form for biliary excretion. Reduced activity causes Gilbert syndrome (mild, common) and Crigler-Najjar (severe); the same enzyme is inhibited by atazanavir and performs many drug glucuronidations.
  4. conjugated-bilirubin → urobilinogen — via intestinal bacterial deconjugation + reduction; excretion + EHC. Gut bacteria deconjugate and reduce bilirubin to urobilinogen; most exits as stercobilin (stool color) while some is reabsorbed (enterohepatic circulation) and renally excreted as urobilin (urine color). Biliary obstruction → pale stool with dark urine.

Known Modulators

References