title: 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 DMA(V)-induced urinary bladder injury in rats. The treatment solutions--DMA(V) 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 DMA(V) 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 DMA(V) and NAC (high dose) cotreated group. These results suggest that cotreatment with NAC enhanced DMA(V)-induced urinary bladder injury and that the effects may be mediated by excess oxidative stress and ERK signaling.
authors.affiliation: The Institute of Environmental Toxicology, Ibaraki, Japan. n.takahashi@iet.or.jp
authors.forename: Naofumi
authors.initials: N
authors.lastname: Takahashi
authors.forename: Toshinori
authors.initials: T
authors.lastname: Yoshida
authors.forename: Aya
authors.initials: A
authors.lastname: Ohnuma
authors.forename: Haruka
authors.initials: H
authors.lastname: Horiuchi
authors.forename: Katsumi
authors.initials: K
authors.lastname: Ishitsuka
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kashimoto
authors.forename: Maki
authors.initials: M
authors.lastname: Kuwahara
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Nakashima
authors.forename: Takanori
authors.initials: T
authors.lastname: Harada
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D002101:Cacodylic Acid / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D011916:Rats, Inbred F344; D001745:Urinary Bladder Diseases / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019459:Urothelium / Q000187:drug effects
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D002101:Cacodylic Acid; D000111:Acetylcysteine