Monomethylarsonous Acid (MMA^III) and Arsenite:  LD₅₀ in Hamsters and In Vitro Inhibition of Pyruvate Dehydrogenase

Abstract

Monomethylarsonous acid (MMA(III)), a metabolite of inorganic arsenic, has received very little attention from investigators of arsenic metabolism in humans. MMA(III), like sodium arsenite, contains arsenic in the +3 oxidation state. Although we have previously demonstrated that it is more toxic than arsenite in cultured Chang human hepatocytes, there are no data showing in vivo toxicity of MMA(III). When MMA(III) or sodium arsenite was administered intraperitoneally to hamsters, the LD(50)s were 29.3 and 112.0 micromol/kg of body wt, respectively. In addition, inhibition of hamster kidney or purified porcine heart pyruvate dehydrogenase (PDH) activity by MMA(III) or arsenite was determined. To inhibit hamster kidney PDH activity by 50%, the concentrations (mean +/- SE) of MMA(III) as methylarsine oxide, MMA(III) as diiodomethylarsine, and arsenite were 59.9 +/- 6.5, 62.0 +/- 1.8, and 115.7 +/- 2.3 microM, respectively. To inhibit activity of purified porcine heart PDH activity by 50%, the concentrations (mean +/- SE) of MMA(III) as methylarsine oxide and arsenite were 17.6 +/- 4.1 and 106.1 +/- 19.8 microM, respectively. These data demonstrate that MMA(III) is more toxic than inorganic arsenite, both in vivo and in vitro, and call into question the hypothesis that methylation of inorganic arsenic is a detoxication process.

A C⋅As lyase for degradation of environmental organoarsenical herbicides and animal husbandry growth promoters

“…MAs(III) is more toxic than inorganic As(III) in Chang human hepatocytes (15) and hamsters (16). We showed that it is more toxic in Escherichia coli cells as well (Fig.…”

Examination of the effects of arsenic on glucose homeostasis in cell culture and animal studies: Development of a mouse model for arsenic-induced diabetes

“…Notably, DMAs III inhibited GLUT4 translocation in insulin-activated adipocytes by a mechanism independent of PKB/Akt phosphorylation. Results from other laboratories suggest that metabolites of iAs may also interfere with glucose metabolism by inhibiting α-ketoglutarate dehydrogenase or pyruvate dehydrogenase (Boquist et al, 1988;Petrick et al, 2001), two rate limiting enzymes involved in the oxidative metabolism of carbohydrates. However, it is unclear whether concentrations of iAs metabolites in tissues of chronically exposed individuals can reach levels necessary for inhibition of these enzymes.…”

Oxidation state specific generation of arsines from methylated arsenicals based on l-cysteine treatment in buffered media for speciation analysis by hydride generation-automated cryotrapping-gas chromatography-atomic absorption spectrometry with the multiatomizer

“…Human metabolism of iAs involves the reduction of As(V) to As(III) and the oxidative methylation of As(III)-species that yields methylated arsenicals containing either As(III) or As(V) [1][2][3]. Toxicities of tri-and pentavalent iAs and methylated arsenicals differ significantly [4][5][6]. Therefore, developing methods for the oxidation state specific speciation analysis of As in biological matrices has become a key issue for As toxicology and analytical chemistry.…”