Pharmacokinetics, Metabolism, and Carcinogenicity of Arsenic

Pott, Wendy A; Benjamin, Stephen A.; Yang, Raymond S. H.

doi:10.1007/978-1-4613-0107-3_3

Cited by 63 publications

(44 citation statements)

References 211 publications

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“…In support of this, inorganic arsenic alone has been reported to be negative as a carcinogen in animal studies, whereas arsenic was recently reported to be strongly co-carcinogenic in the presence of UV irradiation and other mutagen-carcinogens. 33,34 Decreased DNA repair has been associated previously with increased susceptibility to cancer. 35 For example, decreased DNA repair activity increases skin cancer susceptibility.…”

Section: Discussionmentioning

confidence: 99%

Decreased DNA repair gene expression among individuals exposed to arsenic in United States drinking water

Andrew

Karagas

Hamilton

2003

Intl Journal of Cancer

150

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Arsenic is well established as a human carcinogen, but its precise mechanism of action remains unknown. Arsenic does not directly damage DNA, but may act as a carcinogen through inhibition of DNA repair mechanisms, leading indirectly to increased mutations from other DNA damaging agents. The molecular mechanism underlying arsenic inhibition of nucleotide excision repair after UV irradiation (Hartwig et al., Carcinogenesis 1997;18:399 -405) is unknown, but could be due to decreased expression of critical genes involved in nucleotide excision repair of damaged DNA. This hypothesis was tested by analyzing expression of repair genes and arsenic exposure in a subset of 16 individuals enrolled in a population based case-control study investigating arsenic exposure and cancer risk in New Hampshire. Toenail arsenic levels were inversely correlated with expression of critical members of the nucleotide excision repair complex, ERCC1 (r 2 ‫؍‬ 0.82, p < 0.0001), XPF (r 2 ‫؍‬ 0.56, p < 0.002), and XPB (r 2 ‫؍‬ 0.75, p < 0.0001). The internal dose marker, toenail arsenic level, was more strongly associated with changes in expression of these genes than drinking water arsenic concentration. Our findings, based on human exposure to arsenic in a US population, show an association between biomarkers of arsenic exposure and expression of DNA repair genes. Although our findings need verification in a larger study group, they are consistent with the hypothesis that inhibition of DNA repair capacity is a potential mechanism for the co-carcinogenic activity of arsenic.

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Section: Discussionmentioning

confidence: 99%

Decreased DNA repair gene expression among individuals exposed to arsenic in United States drinking water

Andrew

Karagas

Hamilton

2003

Intl Journal of Cancer

150

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“…Arsenic-induced oxidative stress or redox disturbance (17,(19)(20)(21) contributes to DNA damage (22)(23)(24), chromosomal aberrations (25), and protein expression alterations (22,26). However, its role in arsenic carcinogenesis is not completely understood.…”

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confidence: 99%

Sodium arsenite-induced stress-related gene expression in normal human epidermal, HaCaT, and HEL30 keratinocytes.

Trouba

Geisenhoffer

Germolec

2002

Environ Health Perspect

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Arsenic is a carcinogen that poses a significant health risk in humans. Based on evidence that arsenic has differential effects on human, rodent, normal, and transformed cells, these studies addressed the relative merits of using normal human epidermal keratinocytes (NHEK) and immortalized human (HaCaT) and mouse (HEL30) keratinocytes when examining stressinduced gene expression that may contribute to carcinogenesis. We hypothesize that redox-related gene expression is differentially modulated by arsenic in normal versus immortalized keratinocytes. To test the hypothesis, we exposed keratinocytes to sodium arsenite for 4 or 24 hr, at which time serine threonine kinase-25 (

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“…Inorganic arsenic (arsenite and arsenate) is a ubiquitous environmental contaminant that has long been classified as a human carcinogen but its carcinogenic effects have not been conclusively demonstrated in laboratory animals [1][2][3]. Most of the animal experiments showed negative results and some reported a decrease in tumor induction by arsenic alone [1][2][3][4].…”

Section: Arsenic and Its Co-carcinogenicitymentioning

confidence: 99%

“…Most of the animal experiments showed negative results and some reported a decrease in tumor induction by arsenic alone [1][2][3][4]. Unlike classical carcinogens, arsenic fails to induce point mutations in bacterial or mammalian cells [3][4][5][6][7].…”

Section: Arsenic and Its Co-carcinogenicitymentioning

confidence: 99%

“…By contrast, considerable evidence has pointed to arsenic promoting mutagenesis/carcinogenesis, both in in vivo bioassays and in in vitro cell culture systems. At nontoxic concentrations, co-mutagenic effects of arsenic with X-rays, ultraviolet (UV) radiation, or alkylating agents have been repeatedly observed [3][4][5][6][7]. Therefore, it is reasonable to consider that arsenic acts as a co-carcinogen, although some arsenic compounds have been shown to act as complete carcinogens in a few animal models [1].…”

Section: Arsenic and Its Co-carcinogenicitymentioning

confidence: 99%

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Inhibition of nucleotide excision repair by arsenic

et al. 2012

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Inhibition of DNA repair is one proposed mechanism for the co-mutagenicity/co-carcinogenicity of arsenic. This review summarizes the current literature on the effects of arsenic compounds on nucleotide excision repair (NER). Several possible mechanisms for the observed NER inhibition have been proposed. Modulation of the expression of NER proteins has been considered to be one possibility of impairing the NER process. However, data on the effects of arsenic on the expression of NER proteins remain inconsistent. It is more likely that arsenic inhibits the induction of accessory or other key proteins involved in cellular control of DNA repair pathways, such as p53. For example, arsenic affects p53 phosphorylation and p53 DNA binding activity, which could regulate NER through transcriptional activation of downstream NER genes. Although it is important to study possible direct inactivation of NER proteins by arsenic binding, indirect inactivation of proteins having thiol residues critical to their function or zinc finger proteins cannot be negated. For example, nitric oxide (NO) induced in arsenic-treated cells serves as a specific inhibitor of NER, possibly through NO-induced S-nitrosylation of proteins related to DNA repair. Poly(ADP-ribose) polymerase-1, a zinc finger protein implicated in both NER and base excision repair (BER), deserves special attention because of its involvement in NO production and its broad range of protein substrates including many repair enzymes.

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Pharmacokinetics, Metabolism, and Carcinogenicity of Arsenic

Cited by 63 publications

References 211 publications

Decreased DNA repair gene expression among individuals exposed to arsenic in United States drinking water

Decreased DNA repair gene expression among individuals exposed to arsenic in United States drinking water

Sodium arsenite-induced stress-related gene expression in normal human epidermal, HaCaT, and HEL30 keratinocytes.

Inhibition of nucleotide excision repair by arsenic

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