A 28-year-old woman presents with acute abdominal pain, confusion, hyponatremia, and reddish urine after starting oral contraceptive pills. Urine porphobilinogen (PBG) is markedly elevated. The molecular mechanism by which OCP triggers an acute attack involves:
- A Direct inhibition of ALA synthase-1 (ALAS1) by estrogen metabolites
- B Induction of hepatic CYP450 enzymes via PXR/AhR nuclear receptors, consuming heme and derepressing ALAS1 ✓
- C Increased urinary porphyrin excretion by direct renal tubular mechanism
- D Inhibition of heme oxygenase, increasing free heme levels
Explanation
In acute intermittent porphyria (AIP) and related acute hepatic porphyrias, the rate-limiting enzyme ALAS1 is normally repressed by the free heme pool in hepatocytes. Drugs that induce CYP450 enzymes (via PXR/pregnane X receptor or AhR) — including oral contraceptives, barbiturates, and sulfonamides — consume hepatic heme as a CYP450 prosthetic group. This depletes the free heme pool, derepressing ALAS1, flooding the pathway with aminolevulinic acid (ALA) and PBG that accumulate due to the partial enzymatic block. Elevated PBG in urine is the diagnostic hallmark of acute attacks.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.