Dose-dependent effects on tissue distribution and metabolism of dimethylarsinic acid in the mouse after intravenous administration

Most mammals methylate inorganic arsenic to dimethylarsinic acid (DMA). Thi s organic arsenical causes organ-specific toxicity and is a multi-organ tum or promoter. The objective of this study was to examine whether dose could affect the distribution and metabolism of DMA. Female B6C3F1 mice (3-4/time point) were administered 1.11 or 111 mg/kg of DMA (1 mu Ci of [C-14] or un labeled) intravenously and killed serially (5-480 min). Blood was separated into plasma and red blood cell fractions and liver, kidney and lung were r emoved, weighed and homogenized. Tissue samples were oxidized and analyzed for DMA-derived radioactivity. Blood and several organs of the non-radioact ive DMA-treated animals were digested in acid and analyzed by hydride gener ation atomic absorption spectrophotometry for DMA and metabolites. Concentr ation-time profiles showed a biexponential decrease of DMA-derived radioact ivity in all tissues examined. Kidney had the highest concentration (1-20% dose/gm) of radioactivity of all tissues up to 60 min post-administration. Concentration of radioactivity was greater in plasma than red blood cells a t 5 and 15 min and then was similar for the remaining time points. A dose-d ependent effect on the concentration of radioactivity was observed in the l ung. The retention of radioactivity in the lung was altered compared with l iver and kidney, with a much longer t(1/2 beta) and a disproportionate incr ease in area under the curve with increased dose. No methylated or demethyl ated products of DMA were detected in blood or any organ up to 8 h post-exp osure. The dose-dependent distribution of DMA in the lung may have a role i n the toxic effects DMA elicits in this organ. (C) 2000 Elsevier Science Ir eland Ltd. All rights reserved.