Correlation of pulmonary arsenic metabolism and toxicity

Abstract

In lung preparations, As(V) was reduced to As(III) [first order rate constant of 0.0104/min]; As(III) was oxidized to As(V) [first order rate constant of 0.005/min], methylated to MMA [K(m) = 5.383μM, V(max) = 0.00031 μmol/liter/min/mg], and complexed with GSH; MMA was converted to DMA [K(m) = 63.4 μM, V(max) = 0.0000384 μmol/liter/min/mg]; and arsine was oxidized to As(III) and As(V) and methylated. Toxicity of As(III), As(V), MMA, DMA, and arsine was assessed by measuring effects on cell and slice viability hsp32 induction, and production of DNA single strand breaks. Because all species of arsenic did not produce effects, it was possible to deduce an "active" form of arsenic from these studies. Pulmonary arsenic metabolism was modeled using SIMUSOLV. This model indicated that arsine disposition cannot be explained solely by oxidation to As(III) before methylation or further oxidation occurs. The concentration of arsenic species present in toxicity studies were predicted with this model and correlated to observed effects. There was good correlation between reduction of As(V) to As(III) with toxicity and hsp32 induction. However, the effects observed for arsine did not correlate with oxidation to arsenite.