Liver tumorigenicity of trimethylarsine oxide in male Fischer 344 rats--association with oxidative DNA damage and enhanced cell proliferation

Abstract

Arsenic is a notorious environmental toxicant known to be carcinogenic for the skin, lung and urinary bladder in human beings. The carcinogenicity of trimethylarsine oxide (TMAO), one organic metabolite of inorganic arsenics in humans and experimental animals, was investigated here in male Fischer 344 rats in a 2-year carcinogenicity test. TMAO was administered to a total of 129 male rats ad libitum at concentrations of 0 (Control), 50 or 200 p.p.m. in the drinking water. In animals that died or were killed from the 87th week until the end of 104th week, incidences of hepatocellular adenomas were 14.3, 23.8 and 35.6% in the 0, 50 and 200 p.p.m.-treated groups, respectively; the multiplicities were 0.21, 0.33 and 0.53. Both were significantly increased in the 200 p.p.m.-treated group. While a variety of other tumors developed in various organs, they were present in all groups, including the controls, and were histologically diagnosed as those known to occur spontaneously in F344 rats. To test the contribution of reactive oxygen species (ROS) to TMAO tumorigenicity in the liver, 8-hydroxydeoxyguanosine (8-OHdG) formation was assessed by high performance liquid chromatography. The 8-OHdG values for the 200 p.p.m. TMAO group were significantly higher than those for the control group. Furthermore, as assessed by the proliferating cell nuclear antigen index, cell proliferation in the normally appearing parenchyma was elevated by the TMAO treatment. These results indicate that TMAO exerts liver tumorigenicity with possible mechanistic roles for oxidative DNA damage and enhanced cell proliferation.

Mitochondrial Damage Mediates Genotoxicity of Arsenic in Mammalian Cells

“…We further showed that hydroxyl radicals, generated through a superoxide-mediated process involving hydrogen peroxide, play an important role in mediating the genotoxic effects of arsenic (13). These findings are consistent with the reports stipulating the functional role of oxidants in mediating the biological effects of arsenite by linking glutathione content (14), heme oxygenase (15,16), oxidative DNA damage (12,17), and metallothionine (18) to the end points being examined. However, the origin of these oxyradical species and the pathways involved in the generation of other secondary radical species are not known.…”

Commonalities in Metabolism of Arsenicals

“…In addition, two methylated arsenicals containing As V (dimethylarsinic acid and trimethylarsine oxide) are complete carcinogens in rats. [9,10] Hence, the conversion of iAs to methylated metabolites is an activation process [11] and methylated arsenicals derived from the metabolism of other arsenicals should be considered in assessing the risk associated with exposure to these arsenicals. (1), (3), (5), and (7) convert As V to As III and Reactions (2), (4), and (6) are oxidation methylation reactions.…”

“…As noted above, trimethylarsine oxide is a liver carcinogen in rats. [10] AS3MT catalyzes conversion of trimethylarsine oxide to trimethylarsine, [7] a volatile genotoxic species. [22] Chickens treated with arsenocholine exhale a strong garlic-like odor consistent with trimethylarsine expiration; [23] thus, the chicken orthologue of mammalian AS3MT gene (J. Li et al, in preparation) may catalyze the final reductive step in this pathway.…”

Metabolism and toxicity of arsenic in human urothelial cells expressing rat arsenic (+3 oxidation state)-methyltransferase

“…Methylated pentavalent arsenicals, methylarsonic acid (MAs V ), dimethylarsinic acid (DMAs V ), and TMAs V O, which are less acutely toxic than either arsenate (iAs V ) or arsenite (iAs III ) (Yamauchi and Fowler, 1994), are thought to be detoxification products. However, unlike iAs species, DMAs V and TMAs V O at high doses are complete carcinogens in adult rats (Shen et al, 2003;Wei et al, 1999). In contrast, methylated trivalent arsenicals, methylarsonous acid (MAs III ) and dimethylarsonous acid (DMAs III ), are more toxic than iAs in vivo (Petrick et al, 2001) and are more potent than iAs as enzyme inhibitors (Lin et al, 2001;Petrick et al, 2001;, cytotoxins (Petrick et al, 2000;Styblo et al, 2000, and as modulators of cell signaling pathways (Drobná et al, 2003;.…”