The enhancing effect of the antioxidant N-acetylcysteine on urinary bladder injury induced by dimethylarsinic acid

Abstract

Dimethylarsinic acid (DMA V), the major excreted metabolite of inorganic arsenic, is carcinogenic to the rat urinary bladder. Oxidative stress has been proposed as one possible mechanism of DMA V-induced carcinogenesis. The authors determined whether the antioxidant N-acetylcysteine (NAC) modifies DMAV-induced urinary bladder injury in rats. The treatment solutions-DMAV at 10 mg/kg, NAC at 90 or 1.6 mg/kg (high or low dose, respectively), and their combination-were intravesically instilled into female F344 rats over two hours under pentobarbital anesthesia. The treatment was conducted twice with an interval of three days. All animals were euthanized one day after the second treatment. NAC (low dose) alone did not induce histopathological changes or increase 5-bromo-2′-deoxyuridine (BrdU) labeling index in urothelial cells. Both DMA V and NAC (high dose) induced a weak neutrophil infiltration and an increase in the BrdU labeling index; these pathological changes were enhanced by the combined treatment of DMAV and NAC (high or low dose). Increased oxidative stress and urothelial cell hyperplasia with evidence of activated p44/42 MAPK (ERK1/2) and cyclin D1 were found in the DMAV and NAC (high dose) cotreated group. These results suggest that cotreatment with NAC enhanced DMAV-induced urinary bladder injury and that the effects may be mediated by excess oxidative stress and ERK signaling. © Society of Toxicologic Pathology 2011.