Rhodanese: The Cyanide Detoxification Enzyme That Can't Save You from Poisoning

Rhodanese (thiosulfate sulfurtransferase, EC 2.8.1.1) is a mitochondrial enzyme found primarily in the liver, kidney, and adrenal cortex. It catalyzes the transfer of a sulfane sulfur atom from thiosulfate (S₂O₃²⁻) to cyanide (CN⁻), producing thiocyanate (SCN⁻) and sulfite. Thiocyanate is orders of magnitude less toxic than cyanide and is readily excreted in urine. ## Why It Can't Prevent Acute Poisoning Despite being the body's primary cyanide detoxification pathway, rhodanese cannot prevent acute cyanide poisoning for two critical reasons: 1. **Substrate limitation**: The reaction requires thiosulfate, which is scarce in vivo. Without an external supply, rhodanese quickly runs out of substrate. 2. **Speed mismatch**: Cyanide blocks Cytochrome c Oxidase: The Final Enzyme in Cellular Respiration (Complex IV) in Mitochondria: The Powerhouse Organelles with Their Own DNA, causing histotoxic hypoxia within minutes — far faster than rhodanese can clear the cyanide load. ## Clinical Antidote Strategy Because rhodanese alone is too slow, clinical cyanide treatment uses a two-step approach: first, nitrites convert hemoglobin to methemoglobin, which sequesters cyanide as cyanomethemoglobin — buying time. Then administered sodium thiosulfate provides substrate for rhodanese to complete the detoxification. Alternatively, hydroxocobalamin (vitamin B12a) directly chelates cyanide to form non-toxic cyanocobalamin. ## The Mithridatism Myth Rhodanese's existence is sometimes cited to support the myth that Mithridatism: Building Poison Tolerance Through Repeated Exposure (building poison immunity through small doses) works for cyanide. It doesn't — rhodanese cannot be meaningfully upregulated through repeated exposure, and the enzyme's throughput ceiling means larger doses remain lethal regardless of prior exposure.