Effect of phosphate transporter and methylation inhibitor drugs on the disposition of arsenate and arsenite in rats.

Abstract

Arsenate (AsV) is biotransformed into the more toxic arsenite (AsIII) and monomethylarsonous acid (MMAsIII), but it is unknown how to decrease production of these harmful metabolites. We investigated the effects of foscarnet and fosfomycin, drugs interacting with the phosphate transporter, on biotransformation of AsV, an analog of inorganic phosphate. The effects of entacapone, an inhibitor of catechol-O-methyl transferase (COMT), and nitrous oxide, an inactivator of methylcobalamin, were also tested on the formation of MMAsIII from AsIII in order to clarify the role of COMT and methylcobalamin in biomethylation of AsIII. Arsenic in bile and urine of control and treated rats receiving AsV or AsIII was speciated by HPLC-HG-AFS. In AsV-injected rats, foscarnet, but not fosfomycin, increased the urinary excretion of AsV and decreased the biliary and urinary excretion of AsIII as well as biliary excretion of MMAsIII. In AsIII-injected rats, however, foscarnet failed to influence the excretion of AsIII and its metabolites, suggesting that this drug inhibits the hepatic uptake and renal reabsorption of AsV, thereby decreasing formation of AsIII and MMAsIII from AsV. Entacapone or nitrous oxide pretreatment slightly or not at all influenced the biliary excretion of MMAsIII and urinary excretion of dimethylarsinic acid (DMAsV) in AsIII-injected rats. In contrast, periodate-oxidized adenosine, an inhibitor of S-adenosylmethionine-dependent methyltransferases, nearly abolished appearance of methylated arsenic metabolites in bile and urine. Thus, foscarnet facilitates urinary clearance of AsV and decreases formation of toxic AsIII and MMAsIII, indicating that this drug may be used to promote elimination and counter toxification of AsV. Because entacapone and nitrous oxide influenced the excretion of MMAsIII and DMAsV negligibly, neither COMT nor methylcobalamin appears to be involved in arsenic methylation in rats.