Decreased serum concentrations of nitric oxide metabolites among Chinese in an endemic area of chronic arsenic poisoning in inner Mongolia

Pi, Jingbo; Kumagai, Yoshito; Sun, Guifan; Yamauchi, Hiroshi; Yoshida, Toshihide; Iso, Hiroyasu; Endo, Akiko; Yu, Luyang; Yuki, Koichi; Miyauchi, Takashi; Shimojo, Naoki

doi:10.1016/s0891-5849(00)00209-4

Cited by 166 publications

(103 citation statements)

References 26 publications

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“…The arsenic concentration used in this study is comparable to human blood arsenic levels found in chronic arsenosis patients in Inner Mongolia, China, where arsenic-induced skin lesions and cancers are common [22]. After 28 weeks of continuous arsenic exposure, the arsenic-treated cells exhibited unique morphological alterations with the frequent occurrence of giant multinuclear cells (Fig.…”

Section: Low Level Chronic Arsenic Treatment Of Hacat Cells Induces supporting

confidence: 56%

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Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Diwan

Sun

et al. 2008

Free Radical Biology and Medicine

158

147

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Arsenic is a well-known human skin carcinogen but the underlying mechanisms of carcinogenesis are unclear. Transcription factor Nrf2-mediated antioxidant response represents a critical cellular defense mechanism, and emerging data suggest that constitutive activation of Nrf2 contributes to malignant phenotype. In the present study when an immortalized, non-tumorigenic human keratinocyte cell line (HaCaT) was continuously exposed to environmentally relevant level of inorganic arsenite (100 nM) for 28 weeks, malignant transformation occurred as evidenced by the formation of highly aggressive squamous cell carcinoma after inoculation into nude mice. To investigate the mechanisms involved, a broad array of biomarkers for transformation were assessed in these arsenic-transformed cells (termed As-TM). In addition to increased secretion of matrix metalloproteinase-9 (MMP-9), a set of markers for squamous differentiation and skin keratinization, including keratin-1, keratin-10, involucrin, and loricrin, were significantly elevated in As-TM cells. Furthermore, As-TM cells showed increased intracellular glutathione, elevated expression of Nrf2 and its target genes, as well as generalized apoptotic resistance. In contrast to increased basal Nrf2 activity in As-TM cells, a diminished Nrf2-mediated antioxidant response induced by acute exposure to high dose of arsenite or tert-butyl hydroxyquinone occurred. The findings that multiple biomarkers for malignant transformation observed in As-TM cells, including MMP-9 and cytokeratins, are potentially regulated by Nrf2 suggest constitutive Nrf2 activation may be involved in arsenic carcinogenesis of skin. The weakened Nrf2 activation in response to oxidative stressors observed in As-TM cells, coupled with acquired apoptotic resistance, would potentially have increased the likelihood of transmittable oxidative DNA damage and fixation of mutational/DNA damage events.

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Section: Low Level Chronic Arsenic Treatment Of Hacat Cells Induces supporting

confidence: 56%

“…Skin hyperkeratosis is common in chronic arsenosis [22]. Importantly, SCC can arise from arsenic-induced hyperkeratotic lesions [36], suggesting dysfunctional keratinization may be critical in arsenic-induced skin carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Diwan

Sun

et al. 2008

Free Radical Biology and Medicine

158

147

View full text Add to dashboard Cite

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“…1) (Lee et al 2003;Tsou et al 2005;Li et al 2007), it depletes GSH -one of the main antioxidant ROS scavengers -and inhibits redox enzymes (catalase, glutathione peroxidase and reductase, thioredoxin reductase, superoxide dysmutase). The disruption of antioxidant defense mechanisms and the blocking of new NO formation further decrease NO bioavailability and increase endothelial dysfunction (Pi et al 2000). It is notable that acute exposure or low doses do actually induce redox enzymes, indirectly confirming their role in As detoxification (Shi et al 2004;Flora 2011).…”

Section: Endothelial Dysfunction: the Link Between As And CV Disease?mentioning

confidence: 96%

Cardiovascular effects of arsenic: clinical and epidemiological findings

Stea

Bianchi

Cori

et al. 2013

Environ Sci Pollut Res

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“…We previously found that prolonged exposure to inorganic arsenic by drinking water caused a reduction of systemic NO production in the residents of an endemic area of chronic arsenic poisoning (Pi et al 2000). Further studies demonstrated that MMA III was a potent inhibitor of eNOS activity (Sumi et al 2005).…”

Section: Resultsmentioning

confidence: 96%

“…Decreased nitric oxide (NO) bioactivity in endothelium is also implicated in the pathophysiology of arsenic poisoning (Kumagai et al 2004). We previously found that prolonged exposure of humans and rabbits to inorganic arsenic in vivo caused a reduction in systemic NO levels (Pi et al 2000(Pi et al , 2003, which is thought to be related to the inactivity of endothelial NO synthase (eNOS). Further studies demonstrated that MMA III was a potent inhibitor of eNOS activity (Sumi et al 2005).…”

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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Decreased serum concentrations of nitric oxide metabolites among Chinese in an endemic area of chronic arsenic poisoning in inner Mongolia

Cited by 166 publications

References 26 publications

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Cardiovascular effects of arsenic: clinical and epidemiological findings

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

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