Methoxyacetic acid and ethoxyacetic acid inhibit mitochondrial function in vitro

Abstract

Ethylene glycol monomethyl ether (EGME) and ethylene glycol monoethyl ether (EGEE) have recently been shown to be potent reproductive toxicants in laboratory animals. The toxicity of these compounds is believed to be due to their metabolites, methoxyacetic acid (MAA) and ethoxyacetic acid (EAA). Since the primary targets of EGME and EGEE appear to be tissues with rapidly dividing cell systems and high rates of respiration and energy metabolism, the effects of these compounds and their proposed metabolites on mitochondria were investigated. At concentrations beginning at 3.85 mM, MAA and EAA inhibited state 3 respiration and the respiratory control ratio (RCR) in hepatic mitochondria with either succinate or citrate/malate as substrates. Cytochrome c oxidase activity was also inhibited by both metabolites at similar concentrations. The effects of MAA, the metabolite from the more potent compound, on testicular mitochondria were found to be comparable. Neither EGME or EGEE appeared to affect mitochondrial function at concentrations as high as 238 or 113 mM, respectively. These results support the hypothesis that the toxicity of EGME and EGEE are due to their metabolites, MAA and EAA, and that these metabolites may exert their effects, in part, on mitochondrial function.

Ashwagandha Leaf Derived Withanone Protects Normal Human Cells Against the Toxicity of Methoxyacetic Acid, a Major Industrial Metabolite

“…Genetic and functional toxicity of MAA, a major metabolite of ester phthalates, has been shown in a variety of in vitro and in vivo model studies [9], [16], [20]–[23]. It has been shown to cause change in gene expression pattern [8], cell environment [22] and mitochondrial function [24]. We had previously shown that Ashwagandha leaf extract (i-Extract) and withanone, a major constituent in the leaf, cause selective killing of cancer cells [25], [26].…”

N‐acetylcysteine prevents MAA induced male germ cell apoptosis: role of glutathione and cytochrome c

“…Expressions of a testicular germ cell‐specific fatty acid‐binding protein and Src (tyrosine kinase pp60) are also increased in response to MAA treatment [10,11]. Exposure to MAA causes depression of mitochondrial respiration [12] and complex formation between Bcl‐w, Bax and Bak in the mitochondria [13]. Calcium channel blockers have been shown to be successful in preventing MAA induced germ cell death in rats [14].…”

2‐Ethoxyethanol [BAT Value Documentation in German language, 1993]

“…Nur unter dem Einfluß der Alkoxyessigsäure wurde eine Veränderung des Energiehaushaltes der Zellen festgestellt (34). Wie sich bei der Untersuchung von Leber-und Keimzell-Mitochondrien zeigte, wird deren Energieumsatz durch 2-Ethoxyessigsäure, nicht jedoch durch 2-Ethoxyethanol gestört (4).…”