A Major Human Arsenic Metabolite, Dimethylarsinic Acid, Requires Reduced Glutathione To Induce Apoptosis

Sakurai, Takeshi; Qu, Wei; Sakurai, Masaaki; Waalkes, Michael P.

doi:10.1021/tx0101604

Cited by 54 publications

(42 citation statements)

References 49 publications

(97 reference statements)

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“…Severe damaging stimuli tended to result in necrosis, and lower grade damaged stimuli tended to cause apoptosis [21][22][23][24][25][26][27][28][29][30] . Recently, Sakurai et al reported that DMAA could induce apoptosis by reducing glutathione (GSH) in vitro [17] . However, the effect of MT on the induction of apoptosis by DMAA in vivo remains elusive.…”

Section: Discussionmentioning

confidence: 99%

“…Recently Liu et al [16] reported that MT-I/II null mice were more sensitive than wild type mice to hepatotoxic and nephrotoxic effects of oral or injected inorganic arsenicals. Sakurai et al [17] reported that DMAA could induce apoptosis by reducing glutathione (GSH) in vitro. However, the effect of MT on induction of apoptosis and the main organic toxicity by DMAA in vivo remain elusive.…”

Section: Introductionmentioning

confidence: 99%

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Protective role of metallothionein (I/II) against pathological damage and apoptosis induced by dimethylarsinic acid

Chen¹,

Gu²,

Chen³

et al. 2003

WJG

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AIM:To better clarify the main target organs of dimethylarsinic acid toxicity and the role of metallothionein (MTs) in modifying dimethylarsinic acid (DMAA) toxicity. METHODS:MT-I/II null (MT -/-) mice and the corresponding wild-type mice (MT +/+ ), six in each group, were exposed to DMAA (0-750 mg/kg body weight) by a single oral injection. Twenty four hours later, the lungs, livers and kidneys were collected and undergone pathological analysis, induction of apoptotic cells as determined by TUNEL and MT concentration was detected by radio-immunoassay. RESULTS:Remarkable pathological lesions were observed at the doses ranging from 350 to 750 mg/kg body weight in the lungs, livers and kidneys and MT +/+ mice exhibited a relatively slight destruction when compared with that in dose matched MT -/-mice. The number of apoptotic cells was increased in a dose dependent manner in the lungs and livers in both types of mice. DMAA produced more necrotic cells rather than apoptotic cells at the highest dose of 750 mg/kg, however, no significant increase was observed in the kidney. Hepatic MT level in MT +/+ mice was significantly increased by DMAA in a dose-dependent manner and there was no detectable amount of hepatic MT in untreated MT -/-mice. CONCLUSION:DMAA treatment can lead to the induction of apoptosis and pathological damage in both types of mice. MT exhibits a protective effect against DMAA toxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protective role of metallothionein (I/II) against pathological damage and apoptosis induced by dimethylarsinic acid

Chen¹,

Gu²,

Chen³

et al. 2003

WJG

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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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“…Studies in recent years demonstrated that these trivalent methylated arsenicals, such as monomethylarsonous acid (MMA III ) and dimethylarsinous acid (DMA III ), have stronger cytotoxicity and genotoxicity than inorganic arsenic itself (Petrick et al 2000;Sakurai et al 2002). Therefore, these active metabolites are regarded to significantly contribute to the adverse effects associated with inorganic arsenic exposure.…”

Section: ó Springer Science+business Media Llc 2007mentioning

confidence: 99%

Monomethylarsonous Acid Induced Cytotoxicity and Endothelial Nitric Oxide Synthase Phosphorylation in Endothelial Cells

Sun

et al. 2007

Bull Environ Contam Toxicol

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Chronic arsenic poisoning is reported to be associated with peripheral and cardiovascular disease, arteriosclerosis, Raynaud's syndrome, hypertension, and Blackfoot disease. Monomethylarsonous acid (MMA III ) is a reactive metabolite of inorganic arsenic and a potent inhibitor of endothelial nitric oxide synthase (eNOS). Arsenic is also reported to phosphorylate eNOS in cultured keratinocyte and Human T cell leukemia Jurkat cells, respectively. In the present study, we examined the cytotoxicity and eNOS phosphorylation by MMA III exposure in cultured bovine aortic endothelial cells (BAEC). Results showed that MMA III is more toxic than arsenite in BAEC cells. The IC 50 values for MMA III and arsenite were determined to be approximately 1.7 and 24.1 lmol/L, respectively. Exposure of BAEC to MMA III (0.75 lmol/L) caused a significant eNOS phosphorylation 15 min after MMA III exposure. However, a complex of MMA III with dithiothreitol (DTT) that lacks the reactivity with vicinal thiols unaffected eNOS phosphorylation. The present study shows that MMA III generated during biomethylation of arsenic is highly toxic in BAEC. Our study also suggests that MMA III could induce the eNOS phosphorylation through modification to cellular thiols of the eNOS enzyme. And the initial up-regulation of eNOS phosphorylation by MMA III seems to be an adaptive response against disruption of eNOS bioactivity during arsenic exposure.

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A Major Human Arsenic Metabolite, Dimethylarsinic Acid, Requires Reduced Glutathione To Induce Apoptosis

Cited by 54 publications

References 49 publications

Protective role of metallothionein (I/II) against pathological damage and apoptosis induced by dimethylarsinic acid

Protective role of metallothionein (I/II) against pathological damage and apoptosis induced by dimethylarsinic acid

Cytolethality of Glutathione Conjugates with Monomethylarsenic or Dimethylarsenic Compounds

Monomethylarsonous Acid Induced Cytotoxicity and Endothelial Nitric Oxide Synthase Phosphorylation in Endothelial Cells

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