Sodium monochloroacetate causes cytotoxic effects, an increased lactate and pyruvate level and induces ultra structural and cytoskeletal alterations in cultured kidney and liver epithelial cells

Abstract

<jats:p> 1 Monochloroacetic acid (MCAA) and its sodium salt, sodium monochloroacetate (SMCA) are widely used in chemical industries as intermediates in the synthesis of carboxymethylcellulose, phenoxyacetic acid, thio-glycolic acid, glycine, indigoid dyes and others. More-over, MCAA has been found as a by-product of the chlorination disinfection of drinking water and as an environmental contaminant of the atmosphere from the photodechlorination reactions of chlorinated hydrocarbons. Little is known about the mode of action of both compounds on the cellular level. From cases of accidental poisoning of man it is known that MCAA accumulates in liver and kidney. 2 In this study, the cytotoxicity of SMCA on cultured liver (Chang liver cells) and kidney epithelial cells of the proximal tubule (Opossum kidney cells) was investigated and its effect on metabolism, ultrastruc-ture and organization of cytoskeleton was examined. 3 Independent from the growth state of the cells (proliferating or quiescent), the results clearly show that SMCA causes a dose-dependent decrease in cell viability after an exposure period of 24 h. In all experiments, proliferating cells were more sensitive than quiescent and confluent cells. Liver cells were less sensitive against SMCA treatment than kidney epithe-lial cells. In contrast to liver cells, kidney cells exhibited a dose-dependent decrease in cell volume. The decrease in cell viability was accompanied by an increase of lactate and pyruvate concentrations released into the culture medium. In the case of Opossum kidney cells, lactate and pyruvate levels increased 5-6-fold, whereas in the case of Chang liver cells the increase was approximately twofold. While the ultrastructure of liver cells remained unaltered after drug treatment, kidney cells exhibited cytoplas-mic vacuolization, membraneous disruption and especially mitochondrial alterations. In accordance with the changes in the ultrastructure of Opossum cells, was the reorganization of cytoskeletal elements with an increased stress fiber network at the basolat-eral surface as well as a partial depolymerization of microtubules and vimentin filaments. A cytoskeletal reorganization was not observed for Chang liver cells after SMCA treatment. 4 The results demonstrate that SMCA causes a dose-dependent cytotoxicity which is accompanied by metabolic, mitochondrial and cytoskeletal alterations in the cells. </jats:p>

Hepatic injury and gluconeogenesis after subcutaneous injection of monochloroacetic acid in rats

“…These clinical results gain support from a study showing that sodium monochloroacetate causes the release of lactate and pyruvate from cultured liver epithelial cells into the culture medium (22). Although lactic acidosis naturally arises in fatal conditions, MCA caused hyperlactemia in the early stage without prodromal symptoms.…”

“…The serum glucose level is maintained by gluconeogenesis in the liver. Some reports have described that MCA causes hyperglycemia, while others have described hypoglycemia (2,22). The difference depends on whether glycogen still exists in the liver.…”

Chloroacetic acid triggers apoptosis in neuronal cells via a reactive oxygen species-induced endoplasmic reticulum stress signaling pathway

“…CA (1.5 mM; the approximate to LD 50 ) also triggered ER stress, 46 which was identified by monitoring several key molecules that are involved in the unfolded protein 47 responses (including the increase in the expressions of p-PERK, p-IRE-1, p-eIF2a, ATF-4, ATF-6, CHOP, 48 XBP-1, GRP 78, GRP 94, and caspase-12) and calpain activity. Transfection of GRP 78-and GRP 94-specific 49 si-RNA effectively abrogated CA-induced cytotoxicity, caspase-3/-7 and caspase-12 activity, and GRP 78 50 and GRP 94 expression in Neuro-2a cells. Additionally, pretreatment with 2.5 mM N-acetylcysteine (NAC; 51 a glutathione (GSH) precursor) dramatically suppressed the increase in lipid peroxidation, cytotoxicity, 52 apoptotic events, calpain and caspase-12 activity, and ER stress-related molecules in CA-exposed cells.…”

Quantification of monofluoroacetate and monochloroacetate in human urine by isotope dilution liquid chromatography tandem mass spectrometry

“…Monochloroacetic acid is quickly absorbed through the skin, acting as a systemic metabolic poison, so much that only 5-15% of body surface exposure to an 80% monochloroacetic acid solution may be toxic [7]. The metabolism of monochloroacetate is not well understood [16], but up to 70% of the monochloroacetate dose has been detected unchanged in urine post-exposure urine [17]. Methods for the identification of MCA in water and biological matrices using liquid-liquid microextraction, derivatization and subsequent identification using solid-phase microextraction coupled with GC with electron capture detection have also been developed [18].…”