Metabolic Poisons (FC)

Metabolic Poisons Simplified Study Guide

1. Arsenic

• Mechanism of Action:
  • Arsenate disrupts glycolysis by replacing phosphate in the G3P dehydrogenase step.
  • This interference prevents ATP generation in the critical "break-even" step of glycolysis.
  • As a result, net ATP production from glycolysis becomes ZERO.
• Additional Inhibitory Effects:
  • Arsenic can also inhibit hexokinase, which slows down glycolysis and overall energy production.
• Targeted Enzymes:
  • Arsenic binds to thiol-containing enzymes, affecting several critical components, including:
  • Pyruvate Dehydrogenase Complex
  • Alpha-ketoglutarate dehydrogenase
  • G3P dehydrogenase
  • Enzymes that utilize lipoamide
• Overall Consequence:
  • The cumulative result of arsenic exposure leads to severe energy failure in cells.

2. Rotenone

• Mechanism of Action:
  • Rotenone blocks Complex I of the Electron Transport Chain (ETC).
  • This blockage prevents the oxidation of NADH, leading to a decrease in NAD+ levels.
• Impact on Metabolic Pathways:
  • Shortages in NAD+ cause glycolysis, the Pyruvate Dehydrogenase complex (PDC), and the Citric Acid Cycle (CAC) to slow down or come to a halt.
  • Although Complex II continues to function, the resultant buildup of NADH shuts down overall metabolism.
• Toxicity:
  • The extreme toxicity associated with rotenone is primarily due to metabolic paralysis induced by its action.

3. Fluoroacetate

• Mechanism of Action:
  • Fluoroacetate is not directly toxic to isolated enzymes of the CAC but undergoes metabolic conversion in cells.
  • It is converted to fluoroacetyl-CoA, which is then transformed into fluorocitrate.
• Impact on the Citric Acid Cycle:
  • Fluorocitrate specifically inhibits aconitase, a key enzyme in the CAC, halting the entire cycle.
• Resulting Consequences:
  • This inhibition leads to an energy collapse and a buildup of citrate within the metabolic pathway.

4. Cyanide, Azide, Carbon Monoxide

• Mechanism of Action:
  • All three compounds inhibit Complex IV of the ETC.
  • Cyanide and azide bind to Fe3+ heme, whereas carbon monoxide binds to Fe2+ heme.
• Treatment for Cyanide Poisoning:
  • Cyanide treatment protocols utilize:
  • Nitrites: Convert hemoglobin to methemoglobin (Fe3+), which effectively binds cyanide, reducing its toxic effects.
  • Thiosulfate: This compound drives the conversion of cyanide into thiocyanate, which is less harmful.
• Considerations:
  • A notable drawback of utilizing methemoglobin is its inability to carry oxygen, which poses a potential risk of hypoxia.
• Lethality:
  • Cyanide is considered more lethal than azide due to:
  • The limited availability of Complex IV compared to the abundance of hemoglobin in circulation.
  • Inhibition of the ETC results in immediate cellular death, contributing to its high toxicity.

5. DNP (2,4-Dinitrophenol)

• Mechanism of Action:
  • DNP functions as a proton uncoupler by transporting protons across the mitochondrial membrane.
  • This uncoupling prevents ATP synthase from utilizing the proton gradient, ultimately wasting energy derived from food.
• Physiological Effects:
  • The use of DNP results in several physiological changes including:
  • Increased metabolic rate
  • Enhanced fat breakdown
  • Increased heat generation (thermogenesis)
  • The phenomenon of thermogenesis arises because proton flow occurs without ATP synthesis, leading to the release of energy as heat.
• Toxicity Concerns:
  • The toxic effects of DNP stem from excessive heat production and resultant energy failure in the body's metabolic processes.

Key Themes

• Many metabolic poisons exhibit similar traits, disrupting essential processes such as electron transport, glycolysis, or the Citric Acid Cycle.
• A common consequence of these toxic agents is the buildup of NADH, leading to a lack of NAD+ and a rapid loss of ATP.
• The culminating effect of these disruptions is catastrophic energy failure in cells, resulting in severe physiological repercussions.