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Dose-dependent interaction of two heavy metals with amiodarone toxicity in Saccharomyces cerevisiae

Iman Halloum1, Houssein Al-Attrache1,2,3, Katia El-Ghoz1

  • 163572Lebanese University, FS1, Rafic Hariri Campus, Beirut. Lebanon.

Toxicology and Industrial Health
|May 5, 2022
PubMed

Insights

Heavy metals like mercury and cadmium interact with amiodarone (AMD) toxicity in yeast. The interaction is dose-dependent, shifting from antagonistic to synergistic, involving oxidative stress and cellular pathways.

Area of Science:

  • Environmental Toxicology
  • Pharmacology
  • Yeast Genetics

Background:

  • Amiodarone (AMD) is an antiarrhythmic drug known to cause idiosyncratic toxicity.
  • Environmental pollutants, such as heavy metals, may influence drug toxicity through pharmacokinetic and pharmacodynamic interactions.
  • Yeast models offer a platform to study cellular responses like oxidative stress and general stress response pathways relevant to drug toxicity.

Purpose of the Study:

  • To investigate the interaction between mercury chloride (HgCl2) and cadmium chloride (CdCl2) with amiodarone (AMD) toxicity in *Saccharomyces cerevisiae*.
  • To determine the dose-dependent nature (synergistic, additive, antagonistic) of these interactions.
  • To elucidate the roles of specific cellular components, including catalase, nutrient sensing, and calcium homeostasis, in modulating these interactions.

Main Methods:

  • Median drug effect analysis using CompuSyn software to determine interaction types.
  • Testing of various concentrations of HgCl2 and CdCl2 in combination with AMD on *Saccharomyces cerevisiae*.
  • Utilizing mutant yeast strains (deficient in catalase *CTT1*, nutrient sensing receptor *GPR1*, and calcium-manganese transporter *PMR1*) to assess genetic influences on toxicity interactions.

Main Results:

  • HgCl2 and CdCl2 exhibited dose-dependent interactions with AMD toxicity, showing potentiation at high concentrations and antagonism at low concentrations.
  • The transition from antagonistic to synergistic interactions was influenced by the *CTT1* gene, indicating a role for catalase in oxidative stress management.
  • Mutations in *GPR1* and *PMR1* altered the concentration thresholds for synergistic interactions, highlighting the involvement of nutrient sensing and calcium homeostasis.

Conclusions:

  • Heavy metals HgCl2 and CdCl2 exhibit complex, dose-dependent interactions with amiodarone toxicity in yeast.
  • Oxidative stress (via catalase), calcium homeostasis, and nutrient sensing pathways significantly modulate the observed toxicological interactions.
  • These findings provide insights into potential environmental influences on drug toxicity and the underlying cellular mechanisms.
Keywords:
Amiodaronecalcium/manganese transportercatalaseheavy metalsnutrient sensing

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