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

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).