Role of thiols in the in-vitro methylation of inorganic arsenic by rat liver cytosol

Abstract

Rat liver cytosol inactivates inorganic arsenic (Asi) through methylation; S-adenosylmethionine is the methyl group donor and reduced glutathione (GSH) is required for full activity. The study of the combined effects of Asi, GSH and other thiols in vitro and the results of our previous in-vivo studies in humans and rats are consistent with a pathway involving the formation of a monomethylated metabolite which is either rapidly further methylated into a dimethylated derivative or is spontaneously oxidized into monomethylarsonic acid (MMA). The dimethylated metabolite gives rise to dimethylarsinic acid. The first methylation reaction is rate limiting, can be stimulated by GSH and is catalyzed by an enzyme different from that which transfers the second methyl group. The latter is sensitive to inhibition by inorganic arsenic. The stimulation of the first methylation reaction by GSH can only be evidenced at high Asi concentration because under these conditions, the second methylating enzyme can be sufficiently inhibited by Asi to allow some accumulation of MMA. The latter may also slow down the first methylation reaction. A large excess of thiol groups may prevent the methylation reactions probably by decreasing the amount of free trivalent arsenic.