Acute intermittent porphyria (AIP) is caused by porphobilinogen deaminase (PBGD) deficiency. Drug-precipitated attacks cause abdominal pain and neuropsychiatric symptoms. The MECHANISM by which certain drugs (e.g., barbiturates) precipitate AIP attacks is:

• A Induction of hepatic ALAS1 (delta-aminolevulinic acid synthase 1) via PXR/AhR transcription factors, increasing demand on the already-reduced PBGD capacity ✓
• B Direct inhibition of PBGD by the drug metabolite, worsening the enzymatic deficiency
• C Inhibition of ferrochelatase by the drug, preventing heme synthesis and relieving feedback suppression of ALAS1
• D Competitive inhibition of porphyrin transport from hepatocytes by drug metabolites causing intracellular accumulation

Explanation

Barbiturates and many other AIP-precipitating drugs (e.g., rifampicin, sulfonamides, alcohol) induce CYP450 enzymes via PXR (and AhR for some). Increased CYP450 apoenzyme synthesis rapidly depletes heme (heme is the prosthetic group); low heme releases ALAS1 from feedback inhibition by heme (ALAS1 is normally inhibited by heme at the mitochondrial import step via the heme-regulatory motif). Induced ALAS1 dramatically increases ALA and PBG synthesis; with PBGD at ~50% capacity (heterozygote), PBG accumulates because the next step cannot process the surge. Accumulated ALA is neurotoxic. The diagnosis is confirmed by urinary PBG and ALA during an attack.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.