Mechanisms of amiodarone (AMD) toxicity are poorly understood and depend on genetic factors and environmental toxicants such as cigarette smoke condensate (CSC) and heavy metals. AMD toxicity compromises its therapeutic use and could affect non-target species in the ecosystem. This study investigates ATP-binding cassette (ABC)-transporters involvement in the interaction of CSC and some of its inorganic components with AMD toxicity using Saccharomyces cerevisiae. Wild‑type and mutant strains were exposed to AMD ± CSC, CdCl₂, or HgCl₂. Growth inhibition and interaction profiles were analyzed using median‑effect and combination index methods. AMD accumulation inside cells was assessed by HPLC-UV. AMD toxicity was enhanced in strains lacking Pdr5, Pdr12, or Yap1. CSC reduced AMD toxicity and decreased AMD amount inside cells. HgCl₂-AMD interaction was additive in the wild-type but shifted to antagonistic or synergistic depending on the concentration and on the deleted gene. CdCl₂-AMD interaction was synergistic in Pdr5 and Bpt1 mutants across all concentrations. In the wild-type and other mutants, interaction patterns shifted from antagonistic at lower concentrations to additive or synergistic at higher concentrations. We conclude that ABC transporters and oxidative stress regulator play important roles in the interaction of environmental toxicants with AMD toxicity, which is complex, dose-dependent involving multiple pathways.

• PMID: 42663676
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Journal Article

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Al-Attrache H, Halloum I, Al-Ashi A, Kleib V, Abdel-Razzak Z

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