Toxicity of a trivalent organic arsenic compound, dimethylarsinous glutathione in a rat liver cell line (TRL 1215)

Abstract

Background and purpose: Although inorganic arsenite (As III ) is toxic in humans, it has recently emerged as an effective chemotherapeutic agent for acute promyelocytic leukemia (APL). In humans and most animals, As III is enzymatically methylated in the liver to weakly toxic dimethylarsinic acid (DMAs V ) that is a major pentavalent methylarsenic metabolite. Recent reports have indicated that trivalent methylarsenicals are produced through methylation of As III and participate in arsenic poisoning. Trivalent methylarsenicals may be generated as arsenical-glutathione conjugates, such as dimethylarsinous glutathione (DMAs III G), during the methylation process. However, less information is available on the cytotoxicity of DMAs III G. Experimental approach: We synthesized and purified DMAs III G using high performance TLC (HPTLC) methods and measured its cytotoxicity in rat liver cell line (TRL 1215 cells). Key results: DMAs III G was highly cytotoxic in TRL 1215 cells with a LC 50 of 160 nM. We also found that DMAs III G molecule itself was not transported efficiently into the cells and was not cytotoxic; however it readily became strongly cytotoxic by dissociating into trivalent dimethylarsenicals and glutathione (GSH). The addition of GSH in micromolar physiological concentrations prevented the breakdown of DMAs III G, and the DMAs III G-induced cytotoxicity. Physiological concentrations of normal human serum (HS), human serum albumin (HSA), and human red blood cells (HRBC) also reduced both the cytotoxicity and cellular arsenic uptake induced by exposure to DMAs III G.

A novel arsenical has antitumor activity toward As2O3-resistant and MRP1/ABCC1-overexpressing cell lines

“…This confirms data showing that exogenous GSH, cysteine and NAC prevented darinaparsin-induced cytotoxicity in a rat liver cell line. 38 However, depletion of GSH by BSO had no effect on darinaparsin-induced apoptosis, whereas it significantly enhanced As 2 O 3 -induced apoptosis. Although surprising, it has been previously shown that BSO does not enhance darinaparsin-induced cell death in hepatocytes and in cultured BALB/c 3T3 cells.…”

Mutant p53 Protein Is Targeted by Arsenic for Degradation and Plays a Role in Arsenic-mediated Growth Suppression

“…As a known carcinogen, arsenic can induce tumors of the skin, bladder, liver, and lung (27)(28)(29)(30). As a meta-estrogen, arsenic promotes mammary carcinogenesis (31). However, arsenic is also a novel promising anticancer agent for treating acute promyelocytic leukemia (APL) 3 and other tumors with mild adverse effects (27)(28)(29)(30).…”

Mechanisms of Arsenic Detoxification and Resistance

“…Some of the intermediate products, MAs(III) and DMAs(III), are more toxic than As(III) Sakurai et al, 2006;Styblo et al, 2000). However, the pentavalent intermediate products, MAs(V) and DMAs(V), are much less toxic than As(III) (Styblo et al, 2000), and the end product, TMA(III), is almost nontoxic (Cullen, 2005).…”