DIFFERENTIAL-EFFECTS OF VARIOUS TRIVALENT AND PENTAVALENT ORGANIC ANDINORGANIC ARSENIC - SPECIES ON GLUCOSE-METABOLISM IN ISOLATED KIDNEY-CELLS

We have compared the acute toxicities of the trivalent arsenic species arsenite, oxophenylarsine (PhAsO), 2-chlorovinyloxoarsine (ClvinAsO), methyloxoarsine (MeAsO), and of the pentavalent arsenic species arsen ate, methyl- and phenylarsonic acid in rat kidney tubules (RKT) and Ma din-Darby canine kidney (MDCK) cells. In RKT, PhAsO (1 mu mol l(-1), 6 0 min) almost completely (>90%) blocked gluconeogenesis without affect ing cell viability as assessed by dye exclusion. In MDCK cells, PhAsO (2 mu mol l(-1)) markedly inhibited glucose uptake (60% of controls) w ithin 30 min, while cell viability, as assessed by formazan formation, was not affected within 180 min. MeAsO and ClvinAsO were similarly ef fective to PhAsO in both RKT and MDCK cells. Estimated IC50 values for the inhibition of gluconeogenesis were 0.55 (PhAsO), 0.69 (ClvinAsO) and 0.99 mu mol l(-1) (MeAsO) and for the inhibition of glucose uptake 1.23 (PhAsO), 2.62 (ClvinAsO) and 6.99 mu mol l(-1) (MeAsO). At longe r storage times, aqueous solutions of MeAsO and of ClvinAsO, but not o f PhAsO, gradually lost toxic activity in RKT and MDCK cells, especial ly at alkaline pH. Concomitantly, a gradual decrease in content as ass essed by HPLC was detected. Roughly 10-fold higher concentrations of a rsenite than of PhAsO were required for comparable effects on gluconeo genesis in RKT, whereas in MDCK cells about 100-fold higher concentrat ions were needed for similar inhibition of glucose uptake. Pentavalent arsenate and phenylarsonate were two orders of magnitude less effecti ve than PhAsO in RKT, while methylarsonate had virtually no influence on gluconeogenic activity, In MDCK cells the pentavalent arsenic speci es showed effects only in the millimolar range. It is concluded (1) th at different mechanisms are involved in the acute toxicity of oxoarsin es and inorganic arsenic and (2) that PhAsO offers advantages as a mod el substance for monosubstituted trivalent arsenicals, because it is m ore stable and more readily detectable.