In acute arsenic poisoning, which of the following is the primary mechanism of cellular toxicity?

Explanation

## Acute Arsenic Poisoning: Mechanism of Toxicity **Key Point:** Arsenic's primary toxic mechanism is binding to sulfhydryl (–SH) groups of essential enzymes and coenzymes, particularly pyruvate dehydrogenase and other mitochondrial enzymes, disrupting cellular respiration and energy production. ### Arsenic's Biochemical Mechanism **High-Yield:** Arsenic (As³⁺) is a trivalent metalloid that forms covalent bonds with sulfhydryl groups in proteins and coenzymes, inactivating them. This is the fundamental basis of arsenic toxicity. ### Key Enzyme Targets 1. **Pyruvate Dehydrogenase Complex** — inhibition blocks the conversion of pyruvate to acetyl-CoA, halting the Krebs cycle 2. **α-Ketoglutarate Dehydrogenase** — inhibition further impairs the Krebs cycle 3. **Lipoic Acid** (cofactor) — arsenic binds to its sulfhydryl groups, rendering it inactive 4. **Thioredoxin and Glutaredoxin** — antioxidant enzymes are inactivated ### Cellular Consequences ```mermaid flowchart TD A["As³⁺ enters cell"]:::action --> B["Binds to -SH groups on enzymes"]:::action B --> C["Pyruvate dehydrogenase inhibited"]:::outcome C --> D["Krebs cycle blocked"]:::outcome D --> E["↓ ATP production"]:::urgent E --> F["Cellular dysfunction & necrosis"]:::urgent B --> G["Antioxidant enzymes inactivated"]:::outcome G --> H["↑ ROS, oxidative stress"]:::urgent ``` **Clinical Pearl:** The gastrointestinal tract is most severely affected in acute poisoning because of high metabolic demand and rapid arsenic absorption. Massive fluid loss from hemorrhagic gastroenteritis leads to hypovolemic shock and death. ### Distinction from Other Heavy Metals | Metal | Primary Mechanism | Target Enzyme | |-------|------------------|---------------| | **Arsenic** | SH-group binding | Pyruvate dehydrogenase, Krebs cycle enzymes | | **Mercury** | SH-group binding | Protein denaturation, CNS toxins | | **Lead** | Inhibits ALA dehydratase | Heme synthesis | | **Cyanide** | Binds Fe³⁺ in cytochrome c oxidase | Electron transport chain | **Mnemonic:** **"SHARP"** — **S**ulfhydryl **H**eavy metals **A**rsenic **R**eact with **P**roteins