Distribution and speciation of arsenic after intravenous administration of monomethylmonothioarsonic acid in rats.
Quite a few new thioarsenicals have recently been found in urine of arsenic-exposed humans and animals, and some of them have been shown to be highly toxic to cells. However, little is known about their toxic effects and metabolism in the body. In order to elucidate the toxic mechanism of thioarsenicals, we further focused on the distribution and metabolism of monomethylmonothioarsonic acid (MMMTA(V)) in rats. MMMTA(V) was synthesized chemically and injected intravenously into rats at the dose of 0.5mg As/kg, followed by speciation analysis of selected organs and body fluids at 10 min and 12h after the injection. MMMTA(V) was excreted into urine in its intact form, and approximately 35% of the dose was recovered in urine at 12h after the injection, suggesting that MMMTA(V) was taken up more effectively by organs/tissues than non-thiolated, monomethylarsonous acid (MMA(V)) previously studied. On the other hand, the liver and kidneys contained arsenic that was in a protein-binding form with free forms of DMA(V) or DMDTA(V) at 10 min, and disappeared at 12h after the injection. Moreover, these bound arsenic species in kidneys were converted back to MMA(V) after oxidation with H(2)O(2), suggesting that the arsenic bound to proteins had been reduced within the body and was in a trivalent oxidation state. In red blood cells (RBCs), most of the arsenic was in the form of DMA(III) bound to hemoglobin (Hb), and approximately 40% of the dose was recovered in RBCs at 12h after injection. These results indicate that arsenic accumulated preferentially in RBCs after being transformed to DMA(III). In addition, we have also discussed the effect of MMMTA(V) on viability of human bladder cancer T24 cells in comparison with MMA(V). Consequently, MMMTA(V) was assumed to be a more toxic arsenic metabolite than non-thiolated MMA(V).
Naranmandura
Hua
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Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. narenman@zju.edu.cn
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D000818:Animals; D001151:Arsenic / Q000737:chemistry / Q000378:metabolism*; D001152:Arsenicals / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001826:Body Fluids / Q000378:metabolism; D002273:Carcinogens / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004912:Erythrocytes / Q000378:metabolism; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014874:Water Pollutants, Chemical / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*
D001152:Arsenicals; D002273:Carcinogens; D014874:Water Pollutants, Chemical; C552934:monomethylmonothioarsonic acid; D001151:Arsenic