In vitro methylation of arsenite by rabbit liver cytosol: effect of metal ions, metal chelating agents, methyltransferase inhibitors and uremic toxins

The methylation of carrier-free ⁷⁴As-arsenite by liver cytosol of Flemish Giant rabbits is highly susceptible to additions of trace elements. In vitro supplementation of essential trace elements like zinc (Zn²⁺), vanadium (V⁵⁺), iron (Fe²⁺), copper (Cu²⁺) and selenate was shown to increase the methylation efficiency. Trivalent metal ions (e.g. Al³⁺, Cr³⁺ and Fe³⁺), Hg²⁺, Tl⁺ and SeO3^2- had a deleterious effect. The inhibitory effect of EDTA, oxime and many divalent cations (Ca²⁺, Mg²⁺, Sr²⁺, ...) suggest a co-factor role for a specific divalent metal ion, possibly Zn²⁺. Chelating agentsused in clinical treatment of acute and chronic inorganic arsenic poisoning lower the methylation capacity of cytosol by rendering the trivalent arsenic unavailable for the methyltransferase enzymes. S-adenosylhomocysteine and periodate-oxidized adenosine, inhibitors of s-adenosylmethionine dependent methylation pathways, inhibit the methylation of arsenite. Pyrogallol, a catechol-O-methyltransferase inhibitor, blocks the action of arsenite- and monomethylarsonic methyltransferase enzymes, suggesting a close structural relationship between the active sites of the different enzymes. Some uraemic toxins, namely oxalate, p-cresol, hypoxanthine, homocysteine and myo-inositol, inhibit arsenic methylation. [ABSTRACT FROM AUTHOR]