Abstract
Recent studies have identified the 8C alkyl chain methylimidazolium ionic liquid 1-octyl-3-methylimidazolium in the environment and its potential to trigger the auto-immune liver disease primary biliary cholangitis. The toxicity of a range of methylimidazolium ionic liquids were therefore examined. Oxygen consumption was rapidly inhibited, with potency increasing with alkyl chain length. This preceded caspase 3/7 induction and DNA fragmentation. Time- and dose-dependent loss of dye reduction capacities reflected these effects, with a >700 fold difference in potency between 2C and 10C alkyl chain liquids. None of the ionic liquids directly inhibited mitochondrial complexes I-IV or complex V (F0F1-ATPase). However, dithionite reduction and ESR spectroscopy studies indicate a one electron reduction of oxygen in the presence of a methylimidazolium ionic liquid, suggesting methylimidazolium ionic liquids function as mitochondrial electron acceptors. However, only longer chain ionic liquids form a non-aqueous phase or micelle under aqueous physiological conditions and lead to increases in reactive oxygen species in intact cells. These data therefore suggest that the longer chain methylimidazolium liquids are toxic in sensitive liver progenitor cells because they both readily integrate within the inner mitochondrial membrane and accept electrons from the electron chain, leading to oxidative stress.
Highlights
Primary biliary cholangitis (PBC) is chronic autoimmune liver dis ease most common in post-menopausal women
Previous work by others in PC12 cells (Li et al, 2012a, 2012b and our own work in liver suggested that oxidative phosphorylation was a target for M8OI based on an inhibition of oxygen consumption by a variety of intact cells (Probert et al, 2018)
Similar though less potent effects were seen with M8OI and HMI with limited measurable effects observed with EMI and BMI as illustrated using a fixed concentration of each ionic liquid (Fig. 2a, right panel)
Summary
Primary biliary cholangitis (PBC) is chronic autoimmune liver dis ease most common in post-menopausal women. Several studies have made associations between the environment and PBC, suggesting there may be an infectious or chemical trigger (Tanaka et al, 2018). The latter includes evidence for an increase in incidence of PBC in those receiving drinking water from one of several regional reservoirs (Triger, 1980); geographic variations in PBC inci dence in an area associated with mining and heavy industry (Prince et al, 2001) and an increased incidence of PBC in those living in close proximity to a Superfund toxic waste site. A recent study from this laboratory investigated the presence of potential toxic chemicals in soils around a landfill site in a region of the UK with higher PBC incidence (Probert et al, 2018; Oskarrson and Wright, 2019; Leitch et al, 2020).
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