COMPARATIVE IN-VITRO METHYLATION OF TRIVALENT AND PENTAVALENT ARSENICALS

Citation
M. Styblo et al., COMPARATIVE IN-VITRO METHYLATION OF TRIVALENT AND PENTAVALENT ARSENICALS, Toxicology and applied pharmacology, 135(2), 1995, pp. 172-178
Citations number
29
Categorie Soggetti
Pharmacology & Pharmacy",Toxicology
ISSN journal
0041008X
Volume
135
Issue
2
Year of publication
1995
Pages
172 - 178
Database
ISI
SICI code
0041-008X(1995)135:2<172:CIMOTA>2.0.ZU;2-D
Abstract
The time course and extent of methylation of 1 mu M arsenite (iAs(III) ), arsenate (iAs(V)), methylarsenite (MeAs(III)), methylarsenate (MeAs (V)), and MeAs(III)-diglutathione complex (MeAs(III)(GS)(2)) were exam ined in an in vitro assay system that contained rat liver cytosol. Pre cursor arsenicals and methylated metabolites were analyzed by thin-lay er chromatography (TLC) or by hydride generation-atomic absorption spe ctrophotometry (HG-AAS). More than 90% of iAs(III) was converted to a dimethylated species (Me(2)As) during a 90-min incubation at 37 degree s C; the amount of monomethylated metabolite was maximal at 15 min. In contrast, only 40% of iAs(V) was dimethylated during a 90-min incubat ion. Comparison of the yields of methylated species in the whole in vi tro assay system as determined by HG-AAS and in an ultrafiltrate prepa red from the in vitro assay system as determined by TLC indicated that nearly 70% of the dimethylated metabolite (possibly Me(2)As(III)) tha t was produced during a 90-min incubation was bound to proteins (>10 k Da). The percentage of protein-bound arsenic in the assay system incub ated at 0 degrees C with trivalent arsenicals was three-to fivefold gr eater than the binding of corresponding pentavalent species. This indi cated that both iAs(III) and trivalent organoarsenicals interact avidl y with proteins. Both MeAs(III) prepared by metabisulfte-thiossulfate reduction of MeAs(V) and a MeAs(III)(GS)2 were quantitatively converte d to Me(2)As during 90-min incubation. In contrast, only 3% of MeAs(V) was dimethylated during this interval. These results suggest that tri valent arsenicals are preferred substrates for methylation reactions a nd that the reduction of As from pentavalent to trivalent states may b e a critical step in the control of the rate of metabolism of As. (C) 1995 Academic Press, Inc.