Metabolism of dimethylarsinic acid in rats: production of unidentified metabolites in vivo

Abstract

AbstractOur previous study revealed that two unidentified metabolites, M‐1 and M‐2, were excreted in urine after long‐term oral administration of dimethylarsinic acid (DMA), the main metabolite of inorganic arsenic. In the present study, we attempted to clarify the mechanism of production of these unknown metabolites. Male F344/DuCrj rats were administered a single dose of DMA (50 mg kg−1) orally or intraperitoneally with or without pretreatment with L‐buthionine‐SR‐sulfoximine (BSO), which inhibits glutathione (GSH) synthesis. Urine was collected by forced urination at various time points after administration of DMA. Arsenic metabolites in urine were analyzed by ion chromatography with inductively coupled plasma mass spectrometry (IC–ICP‐MS). The unidentified metabolites M‐1 and M‐2 were excreted later than elimination of DMA and trimethylarsine oxide (TMAO). GSH depletion decreased in TMAO elimination, suggesting that GSH plays important roles in the methylation of DMA to TMAO in rats. There was no difference in the amount of production of either M‐1 or M‐2 between BSO‐pretreated rats and controls, suggesting that M‐1 and M‐2 cannot be formed during methylation in the liver. The amounts of elimination of M‐1 and M‐2 were less after intraperitoneal administration than after oral administration.Male F344/DuCrj rats were given 100 mg As l−1 DMA via drinking water for 20 weeks. Urine and feces were collected forcibly and were analyzed by IC–ICP‐MS. A new unidentified metabolite, M‐3, was detected only in feces as a metabolite of DMA after 20 weeks exposure to DMA, although M‐1 and M‐2 were found in both urine and feces. The unidentified metabolites M‐1, M‐2, and M‐3 were excreted mainly as fecal metabolites along with unmetabolized DMA. This finding also suggests that M‐1, M‐2, and M‐3 might be produced in the intestinal tract. Copyright © 2001 John Wiley & Sons, Ltd.