Cellular glutathione prevents cytolethality of monomethylarsonic acid.
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.
Sakurai
Teruaki
T
Laboratory of Environmental Chemistry, School of Life Science, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo 192-0392, Japan. sakurai@ls.toyaku.ac.jp
Kojima
Chikara
C
Ochiai
Masayuki
M
Ohta
Takami
T
Sakurai
Masumi H
MH
Waalkes
Michael P
MP
Fujiwara
Kitao
K
D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D001152:Arsenicals / Q000494:pharmacology*; D002330:Carmustine / Q000494:pharmacology; D002384:Catalysis; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004976:Ethacrynic Acid / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002679:Pan troglodytes; D051381:Rats; D011916:Rats, Inbred F344; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D001152:Arsenicals; D004791:Enzyme Inhibitors; D000625:Aminooxyacetic Acid; D005982:Glutathione Transferase; D005978:Glutathione; C020300:monomethylarsonic acid; D004976:Ethacrynic Acid; D002330:Carmustine