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

Drug Chem Toxicol. 1999 Nov;22(4):613-28. doi: 10.3109/01480549908993171.

Abstract

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.

MeSH terms

  • Animals
  • Arsenites / metabolism*
  • Cresols / pharmacology
  • Cytosol / drug effects*
  • Cytosol / metabolism
  • Edetic Acid / pharmacology*
  • Enzyme Inhibitors / pharmacology*
  • Homocysteine / pharmacology
  • Hypoxanthine / pharmacology
  • In Vitro Techniques
  • Inositol / pharmacology
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Metals, Heavy / pharmacology*
  • Methylation
  • Oxalates / pharmacology
  • Pyrogallol
  • Rabbits
  • Radioisotopes
  • S-Adenosylhomocysteine
  • Substrate Specificity
  • Uremia / metabolism

Substances

  • Arsenites
  • Cresols
  • Enzyme Inhibitors
  • Metals, Heavy
  • Oxalates
  • Radioisotopes
  • Pyrogallol
  • Homocysteine
  • 4-cresol
  • Hypoxanthine
  • Inositol
  • S-Adenosylhomocysteine
  • Edetic Acid
  • arsenite