Monomethylarsonous acid (MMA(III)) and arsenite: LD(50) in hamsters and in vitro inhibition of pyruvate dehydrogenase.
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.
Petrick
J S
JS
Department of Pharmacology and Toxicology, and Center for Toxicology, The University of Arizona, Tucson, Arizona 85721, USA.
Jagadish
B
B
Mash
E A
EA
Aposhian
H V
HV
D000818:Animals; D001152:Arsenicals / Q000009:adverse effects*; D018053:Arsenites / Q000633:toxicity*; D006224:Cricetinae; D006321:Heart; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D007928:Lethal Dose 50; D008297:Male; D008647:Mesocricetus; D008745:Methylation; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D013552:Swine; D013723:Teratogens / Q000633:toxicity*
D001152:Arsenicals; D018053:Arsenites; D011768:Pyruvate Dehydrogenase Complex; D013723:Teratogens; C020300:monomethylarsonic acid; C015001:arsenite