The role of glutathione in the metabolism of diphenylarsinic acid in rats

Abstract

Diphenylarsinic acid (DPAA^V) is a chemical precursor as well as a degradation product of arsenic-containing chemical weapons such as Clark 1 (diphenylarsine chloride) and Clark 2 (diphenylarsine cyanide). Compared to inorganic arsenicals, toxicological findings on DPAA^V are limited. To elucidate the mechanism of DPAA^V toxicity, we investigated the metabolic behavior of DPAA^V in the body. Specifically, we examined the distribution and biliary excretion of DPAA^V and its metabolites in rats orally administered DPAA^V at a dose of 1.0 mg As kg⁻¹ body weight. DPAA^V was excreted in bile, either as the original DPAA^V or as a DPAA–GSH complex (DPAG^III), as determined by HPLC-ICP-MS and HPLC-ESI-MS, with DPAG^III being the main chemical form. Approximately 1.7% and 2.4% of the dose was accumulated in erythrocytes three hours and three days after administration, respectively. Approximately 91% of the dose was excreted in urine and feces as DPAA^V in three days, mostly in the urine. Accumulation of arsenic in erythrocytes was investigated in vitro by incubating (at 37 °C for up to three hours) DPAA^V or DPAG^III with a suspension of rat erythrocytes (10% in Tris-HCl-buffered saline). Approximately 80% of the DPAG^III dose was taken up by erythrocytes within thirty seconds, while approximately 35% of the DPAA^V dose was taken up by erythrocytes after three hours of incubation. DPAG^III was possibly hydrolyzed and converted to trivalent unconjugated arsenical (diphenylarsinous acid, DPA^III), which also was accumulated in erythrocytes. As expected, DPA^III exhibited greater affinity for erythrocyte proteins than did DPAA^V.