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 agents used 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.
De Kimpe
J
J
Laboratory for Analytical Chemistry, University of Ghent, Belgium.
Cornelis
R
R
Vanholder
R
R
D000818:Animals; D018053:Arsenites / Q000378:metabolism*; D003408:Cresols / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects* / Q000378:metabolism; D004492:Edetic Acid / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006710:Homocysteine / Q000494:pharmacology; D019271:Hypoxanthine / Q000494:pharmacology; D066298:In Vitro Techniques; D007294:Inositol / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D019216:Metals, Heavy / Q000494:pharmacology*; D008745:Methylation; D010070:Oxalates / Q000494:pharmacology; D011748:Pyrogallol; D011817:Rabbits; D011868:Radioisotopes; D012435:S-Adenosylhomocysteine; D013379:Substrate Specificity; D014511:Uremia / Q000378:metabolism
D018053:Arsenites; D003408:Cresols; D004791:Enzyme Inhibitors; D019216:Metals, Heavy; D010070:Oxalates; D011868:Radioisotopes; D011748:Pyrogallol; D006710:Homocysteine; C032538:4-cresol; D019271:Hypoxanthine; D007294:Inositol; D012435:S-Adenosylhomocysteine; D004492:Edetic Acid; C015001:arsenite