Blockade and enhancement of glutamate receptor responses in Xenopus oocytes by methylated arsenicals.
In: Archives of Toxicology (Arch.Toxicol.), Jg. 80 (2006) ; Nr. 8, S. 492-501
Zeitschriftenaufsatz / Fach: Chemie
Pentavalent and trivalent organoarsenic compds. belong to the major metabolites of inorg. arsenicals detected in humans. Recently, the question was raised whether the org. arsenicals represent metabolites of a detoxification process or methylated species with deleterious biol. effects. In this study, the effects of trivalent arsenite (AsO33-; iAIII), the pentavalent organoarsenic compds. monomethylarsonic acid (CH3AsO(OH)2; MMAV) and dimethylarsinic acid ((CH3)2AsO(OH); DMAV) and the trivalent compds. monomethylarsonous acid (CH3As(OH)2, MMAIII) and dimethylarsinous acid ((CH3)2As(OH); DMAIII) were tested on glutamate receptors and on voltage-operated potassium and sodium channels heterologously expressed in Xenopus oocytes. Membrane currents of ion channels were measured by conventional two-electrode voltage-clamp techniques. The effects of arsenite were tested in concns. of 1-1,000 mmol/l and the org. arsenical compds. were tested in concns. of 0.1-100 mmol/l. We found no significant effects on voltage-operated ion channels; however, the arsenicals exert different effects on glutamate receptors. While MMAV and MMAIII significantly enhanced ion currents through N-methyl-d-aspartate (NMDA) receptor ion channels with threshold concns. <10 mmol/l, DMAV and DMAIII significantly reduced NMDA-receptor mediated responses with threshold concns. <0.1 mmol/l; iAIII had no effects on glutamate receptors of the NMDA type. MMAIII and DMAV significantly reduced ion currents through a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor ion channels with threshold concns. <10 mmol/l (MMAIII) and <1 mmol/l (DMAV). MMAV and iAIII had no significant effects on glutamate receptors of the AMPA type. The effects of MMAV, MMAIII, DMAV and DMAIII on glutamate receptors point to a neurotoxic potential of these substances.