l-Methionine-dl-sulfoxide Metabolism and Toxicity in Freshly Isolated Mouse Hepatocytes: Gender Differences and Inhibition with Aminooxyacetic Acid

Abstract

ABSTRACT:L-Methionine-dl-sulfoxide (MetO) is an L-methionine (Met) metabolite, but its role in Met metabolism and toxicity is not clear. In this study, MetO uptake, metabolism to Met, cytotoxicity, and glutathione (GSH) and glutathione disulfide (GSSG) status were characterized in freshly isolated mouse hepatocytes incubated at 37°C with 0 to 30 mM MetO for 0 to 5 h. In male hepatocytes, dose-dependent cytotoxicity concomitant with GSH depletion without GSSG formation occurred after exposure to 20 or 30 mM MetO but not after exposure to 10 mM MetO. Interestingly, female hepatocytes exposed to 30 mM MetO showed no cytotoxicity and exhibited increased intracellular GSH levels compared with control hepatocytes.

The biochemical and toxicological significance of hypermethionemia: new insights and clinical relevance

“…Experiments in FIMHs have provided the most recent evidence that Met SO may be enzymatically catalyzed and physiologically significant [12,13]. In one set of studies, male, but not female, FIMHs exposed only to the transaminase inhibitor AOAA showed an unexpected, time-dependent increase in cellular Met- d -O levels compared with control FIMHs (Fig.…”

“…In one set of studies, male, but not female, FIMHs exposed only to the transaminase inhibitor AOAA showed an unexpected, time-dependent increase in cellular Met- d -O levels compared with control FIMHs (Fig. 5) [12]. This result led to the identification of methionine- dl -sulphoxide (MetO) TA as a novel metabolic pathway of interest and suggested that Met S -oxidation and MetO TA may occur in vivo at physiological Met concentrations and have some unidentified physiological role.…”

“…To investigate the potential toxicological role of Met SO, the direct toxicity of MetO was examined using FIMHs [12]. As with Met, male, but not female FIMHs were sensitive to MetO toxicity.…”

“…2) which, like methanethiol, should react rapidly with free sulfhydryl groups. Because MetO toxicity was elicited at similar concentrations as Met (>20 mM) [12], the role of Met sulfoxidation in Met toxicity is likely additive to that of the Met TA metabolites.…”

“…In addition, recently obtained evidence also suggests a role for the Met sulfoxidation (SO) pathway (Fig. 2) in Met metabolism and toxicity [12,13]. …”