S-adenosylmethionine Dependent Methylation Research Articles

In Vitro Methylation of Arsenite by Rabbit Liver Cytosol: Effect of Metal Ions, Metal Chelating Agents, Methyltransferase Inhibitors and Uremic Toxins

ABSTRACTThe 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 SeO32- 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.

Synergy between cisplatin and an inhibitor of S-adenosylmethionine dependent transmethylation in human ovarian adenocarcinoma cells

Selection of cells for resistance to cisplatin results in resistance to arsenite and selenite. Mammalian cells detoxify arsenite and selenite by S-adenosylmethionine dependent methylation. We aimed to investigate whether S-adenosylmethionine dependent methylation is involved in the cellular metabolism of cisplatin. Treatment of human ovarian cancer cells 2008 and the cisplatin-resistant subline 2008/C13*5.25 with the S-adenosylhomocysteine hydrolase inhibitor adenosine-dialdehyde, an indirect inhibitor of transmethylation, resulted in a significant elevation (16-fold in 2008, 6-fold in 2008/C13*5.25) in the cellular content of S-adenosylhomocysteine without changing S-adenosylmethionine. Adenosine dialdehyde synergistically enhanced the cytotoxicity of cisplatin and carboplatin as evidenced by combination indices <1 using the combination index-isobologram method in clonogenic assays with 2008 human ovarian adenocarcinoma cells. However, the cellular accumulation, efflux, steady state content, and the formation of DNA adducts of the cisplatin [H-3]-DEP were not affected by adenosine-dialdehyde. Sodium arsenite was significantly more toxic in mice pretreated with adenosine-dialdehyde, whereas the toxicity of cisplatin remained unchanged. These studies suggest that inhibition of S-adenosylmethionine dependent transmethylation enhanced the toxicity of cisplatin and carboplatin to human ovarian carcinoma cells in vitro without directly affecting the metabolism of either platinum drug.