Preventive mechanism of cellular glutathione in monomethylarsonic acid-induced cytolethality

Sakurai, Takeshi; Ochiai, Masayuki; Kojima, Chikara; Ohta, Takami; Sakurai, Masaaki; Takada, Naoko; Qu, Wei; Waalkes, Michael P.; Himeno, Seiichiro; Fujiwara, Kitao

doi:10.1016/j.taap.2004.11.008

Cited by 32 publications

(24 citation statements)

References 42 publications

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“…As III markedly enhanced the Cys-MTS reaction, and we previously reported that As III also significantly enhanced the GSH-MTS reaction. 18,19 It has still not been clarified why As III enhances these reactions; however, it is believed that this might, at least in part, be related to the mechanism of As III -induced cytolethality or the protective effects of Cys against As III -induced cytolethality. In contrast,…”

Section: Discussionmentioning

confidence: 99%

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Effects of exogenous cysteine on inorganic and organic arsenicals‐induced cytolethality

Sakurai

Kojima

Waalkes

et al. 2006

Applied Organom Chemis

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Inorganic arsenicals are distinctly toxic and carcinogenic to humans. Inorganic arsenite (As III ) and arsenate (As V ) are enzymatically methylated to monomethylarsonic acid (MMAs V ) and dimethylarsinic acid (DMAs V ) in mammals. Recent reports indicate that cytotoxic trivalent methylated arsenicals are produced through methylation of inorganic arsenicals and are involved in arsenic poisoning. Some previous studies have suggested that a typical thiol reagent cysteine (Cys) can reduce pentavalent arsenicals to trivalent arsenicals and might be able to enhance arsenic cytolethality. However, not much is known concerning the effects of exogenous Cys on the cytolethality of arsenicals. In this study, we examined the effects of exogenous Cys on the cytolethality induced by inorganic and organic arsenicals using rat liver cells. Cys prevented inorganic As III -induced cytolethality. In contrast, when more than 5 mM Cys was incubated with millimolar levels of MMAs V or DMAs V , MMAs V -and DMAs V -induced cytolethality significantly increased; this cytolethality might have been caused by the generation of trivalent methylated arsenicals. However, Cys at a concentration of less than 5 mM decreased the MMAs V -and DMAs V -induced cytolethality. These findings suggest that high concentrations of both arsenicals and Cys are required to form trivalent methylated arsenicals and to induce significant cytolethality.

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Section: Discussionmentioning

confidence: 99%

“…18,19 This assay measures the amount of formazan produced by the metabolic conversion of Owen's reagent [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; MTS] by Cys. The MTS is the subject of U.S. patent no.…”

Section: Mts Assaymentioning

confidence: 99%

Effects of exogenous cysteine on inorganic and organic arsenicals‐induced cytolethality

Sakurai

Kojima

Waalkes

et al. 2006

Applied Organom Chemis

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“…DMPO at this con- centration effectively scavenged cellular ROS and did not influence cell viability. 18,22) The addition of DMPO had no effect on the cytolethality or cellular uptake of MMAs-or DMAs-GSH conjugates (Figs. 5, 6).…”

Section: Mmasmentioning

confidence: 99%

“…We previously reported that there were substantial differences between the mechanism of DMAs V -induced cytolethality and that of MMAs V -induced cytolethality, and cellular GSH played different roles in the cytolethality of MMAs V and DMAs V . 8,[17][18][19][20][21][22] GSH may be a key molecule in preventing or inducing arsenic cytolethality. GSH nonenzymatically combines with MMAs V and DMAs V , resulting in the generation of MMAs III DG and DMAs III G. 15,16) The present results suggested that arsenical and GSH concentrations greatly affect the formation and cytolethality of arsenical-GSH conjugates.…”

Section: Mmasmentioning

confidence: 99%

Cytolethality of Glutathione Conjugates with Monomethylarsenic or Dimethylarsenic Compounds

Kojima

Sakurai

Waalkes

et al. 2005

Biological & Pharmaceutical Bulletin

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Arsenic is a metalloid element that is widely distributed in the environment as a natural component of soil and in water as inorganic trivalent (arsenite) or pentavalent (arsenate) forms, 1) and its toxicity has been known since ancient times. In Asia and the Americas, chronic arsenic poisoning has occurred as a result of the consumption of high levels of arsenic-contaminated well water. Epidemiological studies have provided clear evidence that inorganic arsenicals are a human carcinogen with target sites including liver, skin, lung, kidney and urinary bladder.2) However, the mechanism of arsenic-induced impediment is not clear. On the other hand, inorganic arsenite has emerged as a potent chemotherapeutic agent with remarkable efficacy for certain human cancers, such as acute promyelocytic leukemia.3,4) It would thus appear that environmental and iatrogenic exposure to arsenic will continue to be common.In humans and numerous experimental animals, pentavalent arsenate is rapidly reduced to trivalent arsenite. 5) Subsequently, it is enzymatically methylated into organic arsenicals, such as monomethylarsonic acid (MMAs V ) and dimethylarsinic acid (DMAs V ).6) MMAs V and DMAs V are the major organic pentavalent arsenic metabolites in human urine after exposure to inorganic arsenicals. 5,6) It is believed that methylation of inorganic arsenicals results in a reduction in general toxicity, as indicated by their increased in vivo lethal dose in 50% of a population (LD 50 ) and in vitro lethal concentration in 50% of a population (LC 50 ). 7,8) However, recent studies have increasingly suggested that the methylation of inorganic arsenicals is not a universal detoxification mechanism. Some researchers have reported that trivalent methyl arsenicals, such as monomethylarsonous acid (MMAs III ) and dimethylarsinous acid (DMAs III ), were found in urine collected from people who had been exposed to high concentrations of inorganic arsenicals, 9,10) and that synthetic trivalent methyl arsenicals, such as monomethylarsine oxide (MMAs III O) and iododimethylarsine (DMAs III I), are more cytotoxic in vitro than inorganic arsenicals and pentavalent methyl arsenicals.11) Trivalent methyl arsenicals are thought to be generated as arsenical-glutathione conjugates, such as mono-methylarsonous diglutathione (MMAs III DG) and dimethylarsinous glutathione (DMAs III G), in the human body. [12][13][14] It was also reported that reduced glutathione (GSH) nonenzymatically reduces pentavalent methyl arsenicals to trivalent methyl arsenicals in water, thus resulting in the formation of MMAs III DG and DMAs III G in vitro.

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“…However, the toxicity associated with inorganic arsenic oxides limits their use in therapy. Thus, organoarsenic compounds have received more attention because of their lower toxicity as compared with inorganic arsenicals [12,13]. Zingaro and coworkers have reported on the synthesis and application of organic arsenicals as antileukemic agents [14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Syntheses of 1‐thio‐D‐xylose and D‐ribose esters of diorganoarsinous acids and their anticancer activity

Gao

Chen

Tan

et al. 2008

Heteroatom Chemistry

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Preventive mechanism of cellular glutathione in monomethylarsonic acid-induced cytolethality

Cited by 32 publications

References 42 publications

Effects of exogenous cysteine on inorganic and organic arsenicals‐induced cytolethality

Effects of exogenous cysteine on inorganic and organic arsenicals‐induced cytolethality

Cytolethality of Glutathione Conjugates with Monomethylarsenic or Dimethylarsenic Compounds

Syntheses of 1‐thio‐D‐xylose and D‐ribose esters of diorganoarsinous acids and their anticancer activity

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