Lead poisoning inhibits two enzymes in the haem biosynthetic pathway. Which pair of enzymes is inhibited, and what diagnostic metabolites accumulate?

• A ALAS and ferrochelatase — accumulation of protoporphyrin IX and zinc-protoporphyrin
• B ALA dehydratase (ALAD) and ferrochelatase — accumulation of ALA and zinc-protoporphyrin in RBCs ✓
• C Coproporphyrinogen oxidase and PBGD — accumulation of PBG and coproporphyrin
• D Uroporphyrinogen decarboxylase and ferrochelatase — accumulation of uroporphyrin and protoporphyrin

Explanation

Lead inhibits two sulfhydryl-containing enzymes: (1) ALA dehydratase (ALAD, which condenses two ALA to PBG) — the most sensitive enzyme, inhibited at very low blood lead levels; and (2) ferrochelatase (which inserts Fe2+ into protoporphyrin IX). This causes: elevated urinary ALA (proximal to ALAD block) and elevated erythrocyte zinc-protoporphyrin/ZPP (Fe2+ cannot be inserted, so zinc substitutes). ZPP in red cells is the most sensitive routine screening test for lead exposure. Free erythrocyte protoporphyrin (FEP) measurement is an alternative marker.

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

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