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

Abstract

Amiodarone (AMD) is an antiarrhythmic drug that induces idiosyncratic toxicity. Environmental pollutants, including heavy metals, could interact with its toxicity by affecting pharmacokinetics and pharmacodynamics. Other levels of interaction could exist in yeast, such as oxidative stress and the general stress response. In this study, we investigated the interaction of mercury chloride (HgCl₂) and cadmium chloride (CdCl₂) with AMD toxicity on Saccharomyces cerevisiae. Interaction type - synergistic, additive, or antagonistic - was determined by median drug effect analysis using “CompuSyn”. HgCl₂ potentiated AMD toxicity at high doses (≥ 71.4 μm, which yielded more than 60% inhibition). CdCl₂ acted similarly at high doses (≥ 57.9 μm). An antagonistic effect appeared at lower doses with both heavy metals (≤ 49.4 μm for HgCl₂ and AMD; ≤ 18.9 μm for CdCl₂ and AMD). The threshold concentrations (HgCl₂ or CdCl₂ combined with AMD) that switched the interaction from antagonistic to additive, and then to synergistic, were decreased in the yeast strain mutant in catalase (CTT1), suggesting an important role for this enzyme. Moreover, mutation of the nutrient sensing receptor gene GPR1 caused the synergistic interaction of CdCl₂, but not HgCl₂, with AMD to occur at the lowest tested concentrations (1.2 μm). The reverse was obtained with the mutant strain in calcium–manganese transporter gene PMR1, where the synergistic interaction of HgCl₂ with AMD occurred at concentrations (20.7 μm) lower than that of the wild type (71.4 μm). These results demonstrated a dose-dependent interaction between the two heavy metals with AMD toxicity, and the involvement of oxidative stress, calcium homeostasis, and nutrient sensing in the observed interaction.