Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.3.2.3 (glutathione synthetase)
 678 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inorganic arsenicals are clearly toxicants and carcinogens in humans. In mammals, including humans, inorganic arsenic often undergoes methylation, forming compounds such as monomethylarsonic acid (MMAs(V)) and dimethylarsinic acid (DMAs(V)). However, much less information is available on the in vitro toxic potential or mechanisms of these methylated arsenicals, especially MMAs(V). We studied the molecular mechanisms of in vitro cytolethality of MMAs(V) using a rat liver epithelial cell line (TRL 1215). MMAs(V) was not cytotoxic in TRL 1215 cells even at concentrations exceeding 10 mM, but it became weakly cytotoxic and induced both necrotic and apoptotic cell death when cellular reduced glutathione (GSH) was depleted with the glutathione synthase inhibitor, l-buthionine-[S,R]-sulfoximine (BSO), or the glutathione reductase inhibitor, carmustine. Similar results were observed in the other mammalian cells, such as human skin TIG-112 cells, chimpanzee skin CRT-1609 cells, and mouse metallothionein (MT) positive and MT negative embryonic cells. Ethacrynic acid (EA), an inhibitor of glutathione S-transferase (GST) that catalyses GSH-substrate conjugation, also enhanced the cytolethality of MMAs(V), but aminooxyacetic acid (AOAA), an inhibitor of beta-lyase that catalyses the final breakdown of GSH-substrate conjugates, had no effect. Both the cellular GSH levels and the cellular GST activity were increased by the exposure to MMAs(V) in TRL 1215 cells. On the other hand, the addition of exogenous extracellular GSH enhanced the cytolethality of MMAs(V), although cellular GSH levels actually prevented the cytolethality of combined MMAs(V) and exogenous GSH. These findings indicate that human arsenic metabolite MMAs(V) is not a highly toxic compound in mammalian cells, and the level of cellular GSH is critical to its eventual toxic effects.
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PMID:Cellular glutathione prevents cytolethality of monomethylarsonic acid. 1499 80

Inorganic arsenicals are clearly toxicants and carcinogens in humans. In mammals, including humans, inorganic arsenicals often undergo methylation, forming compounds such as dimethylarsinic acid (DMAs(V)). Recent evidence indicates that DMAs(V) is a complete carcinogen in rodents although evidence for inorganic arsenicals as carcinogens in rodents remains equivocal. Thus, we studied the molecular mechanisms of in vitro cytolethality of DMAs(V) using a rat liver epithelial cell line (TRL 1215). DMAs(V) selectively induced apoptosis in TRL 1215 cells; its LC(50) value after 48 h exposure was 4.5 mM. The addition of a glutathione synthase inhibitor, L-buthionine-[S,R]-sulfoximine (BSO), actually decreased DMAs(V)-induced apoptosis. DMAs(V) exposure temporarily decreased cellular reduced glutathione (GSH) levels and enhanced cellular glutathione S-transferase (GST) activity from 6 h after the exposure when the cells were still alive. Also, DMAs(V) exposure activated cellular caspase 3 activity with a peak at 18 h after the exposure when apoptosis began, and BSO treatment completely inhibited this enzyme activity. The additions of inhibitors of caspase 3, caspase 8, and caspase 9 significantly reduced DMAs(V)-induced apoptosis. Taken together, these data indicate that cellular GSH was required for DMAs(V)-induced apoptosis to occur, and activation of cellular caspases after conjugation of DMAs(V) with cellular GSH appears to be of mechanistic significance. Further research will be required to determine the role of intracellular GSH and methylation in the toxicity of arsenicals in chronic arsenic poisoning or in cases where arsenicals are used as chemotherapeutics.
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PMID:Role of glutathione in dimethylarsinic acid-induced apoptosis. 1527 15