## Mechanism of Arsenic Toxicity **Key Point:** Arsenic (trivalent form, As³⁺) binds to sulfhydryl (-SH) groups on cysteine residues in proteins, inactivating critical enzymes involved in cellular respiration and metabolism. ### Molecular Mechanism of Arsenic Poisoning 1. **Arsenic-Sulfhydryl Binding** - Trivalent arsenic (As³⁺) has high affinity for sulfhydryl groups - Forms stable As-S bonds with cysteine residues in proteins - This is a reversible but tight interaction 2. **Enzymes Inhibited by Arsenic** - **Pyruvate dehydrogenase complex** — blocks conversion of pyruvate to acetyl-CoA; impairs aerobic metabolism - **α-ketoglutarate dehydrogenase** — inhibits TCA cycle - **Glyceraldehyde-3-phosphate dehydrogenase** — blocks glycolysis - **Lipoic acid-dependent enzymes** — universal energy metabolism disruption 3. **Cellular Consequences** - Severe ATP depletion - Lactic acidosis (from anaerobic metabolism) - Multi-organ failure (especially GI, cardiovascular, renal) **High-Yield:** The sulfhydryl-binding mechanism explains: - Why **BAL (dimercaprol)** and **DMSA (meso-2,3-dimercaptosuccinic acid)** are effective chelators — they compete for arsenic binding - Why arsenic poisoning causes acute gastrointestinal symptoms (epithelial cell energy failure) - Why chronic arsenic exposure causes peripheral neuropathy (nerve cell ATP depletion) **Clinical Pearl:** The trivalent form (As³⁺) is more toxic than the pentavalent form (As⁵⁺) because it binds sulfhydryl groups more avidly. Pentavalent arsenic is reduced to trivalent in the body, which is why both forms are toxic. **Mnemonic:** **ARSENIC blocks SH** = **A**rsenic binds **S**ulfhydryl groups, **E**nzyme **N**ames (pyruvate dehydrogenase, α-ketoglutarate dehydrogenase), **I**nhibits **C**ellular respiration.
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