Review
Recent Advances in Arsenic Carcinogenesis: Modes of Action, Animal Model Systems, and Methylated Arsenic Metabolites

https://doi.org/10.1006/taap.2001.9157Get rights and content

Abstract

Recent advances in our knowledge of arsenic carcinogenesis include the development of rat or mouse models for all human organs in which inorganic arsenic is known to cause cancer–skin, lung, urinary bladder, liver, and kidney. Tumors can be produced from either promotion of carcinogenesis protocols (mouse skin and lungs, rat bladder, kidney, liver, and thyroid) or from complete carcinogenesis protocols (rat bladder and mouse lung). Experiments with p53+/− and K6/ODC transgenic mice administered dimethylarsinic acid or arsenite have shown some degree of carcinogenic, cocarcinogenic, or promotional activity in skin or bladder. At present, with the possible exception of skin, the arsenic carcinogenesis models in wild-type animals are more highly developed than in transgenic mice. Recent advances in arsenic metabolism have suggested that methylation of inorganic arsenic may be a toxification, rather than a detoxification, pathway and that trivalent methylated arsenic metabolites, particularly monomethylarsonous acid and dimethylarsinous acid, have a great deal of biological activity. Accumulating evidence indicates that these trivalent, methylated, and relatively less ionizable arsenic metabolites may be unusually capable of interacting with cellular targets such as proteins and even DNA. In risk assessment of environmental arsenic, it is important to know and to utilize both the mode of carcinogenic action and the shape of the dose–response curve at low environmental arsenic concentrations. Although much progress has been recently made in the area of arsenic's possible mode(s) of carcinogenic action, a scientific concensus has not yet been reached. In this review, nine different possible modes of action of arsenic carcinogenesis are presented and discussed–induced chromosomal abnormalities, oxidative stress, altered DNA repair, altered DNA methylation patterns, altered growth factors, enhanced cell proliferation, promotion/progression, gene amplification, and suppression of p53.

References (79)

  • H. Hayashi et al.

    Dimethylarsinic acid, a main metabolite of inorganic arsenics, has tumorigenicity and progression effects in the pulmonary tumors of A/J mice

    Cancer Lett.

    (1998)
  • Y. Hu et al.

    Arsenic toxicity is enzyme specific and its affects on ligation are not caused by the direct inhibition on DNA repair enzmes

    Mutat. Res.

    (1998)
  • I. Husain et al.

    Sequences of Escherichia coli uvrA gene and the protein reveal two potential ATP binding sites

    J. Biol. Chem.

    (1986)
  • E.M. Kenyon et al.

    A concise review of the toxicology and carcinogenicity of dimethylarsinic acid

    Toxicology

    (2001)
  • K. Kitchin et al.

    Predictive assay for rodent carcinogenicity using in vivo biochemical parameters: Operational characteristics and complementarity

    Mutat. Res.

    (1992)
  • M.J. Mass et al.

    Arsenic alters cytosine methylation patterns of the promoter of the tumor suppressor gene p53 in human lung cells: A model for a mechanism of carcinogenesis

    Mutat. Res.

    (1997)
  • M. Matsui et al.

    The role of oxidative DNA damage in human arsenic carcinogenesis: Detection of 8-hydroxy-2′-deoxyguanosine in arsenic-related Bowen's disease

    J. Invest. Dermatol.

    (1999)
  • J.S. Petrick et al.

    Monomethylarsonous acid (MMA(III)) is more toxic than arsenite in Chang human hepatocytes

    Toxicol. Appl. Pharmacol.

    (2000)
  • A.M. Salazar et al.

    Induction of p53 protein expression by sodium arsenite

    Mutat. Res.

    (1997)
  • J.W. Yager et al.

    Inhibition of poly(ADP-ribose)polymerase by arsenite

    Mutat. Res.

    (1997)
  • K. Yamanaka et al.

    Induction of DNA damage by dimethylarsine, a metabolite of inorganic arsenics, is for the major part likely due to its peroxyl radical

    Biochem. Biophys. Res. Commun.

    (1990)
  • K. Yamanaka et al.

    The role of orally administered dimethylarsinic acid, a main metabolite of inorganic arsenics, in the promotion and progression of UVB-induced skin tumorigenesis in hairless mice

    Cancer Lett.

    (2000)
  • C.O. Abernathy et al.

    Arsenic: Health effects, mechanisms of actions and research issues

    Environ. Health Perspect.

    (1999)
  • L.L. Arnold et al.

    Effects of dietary dimethylarseinic acid on the urine and urothelium of rats

    Carcinogenesis

    (1999)
  • H.V. Aposhian

    Biochemical toxicology of arsenic

  • H.V. Aposhian et al.

    Occurrence of monomethylarsonous acid in urine of humans exposed to inorganic arsenic

    Chem. Res. Toxicol.

    (2000)
  • G. Beckman et al.

    Chromosome aberrations in workers exposed to arsenic

    Environ. Health Perspect.

    (1977)
  • W. Boonchai et al.

    Expression of p53 in arsenic-related and sporadic basal cell carcinoma

    Arch. Dermatol.

    (2000)
  • J.L. Brown et al.

    Dimethylarsinic acid treatment alters six different rat biochemical parameters: Relevance to arsenic carcinogenesis

    Teratog. Carcinog. Mutagen.

    (1997)
  • K. Castren et al.

    Infrequent p53 mutations in arsenic-related skin lesions

    Oncol. Res.

    (1998)
  • B.W. Cherney et al.

    cDNA sequence, protein structure, and chromosomal location of the human gene for poly (ADP-ribose) polymerase

    Proc. Natl. Acad. Sci. USA

    (1987)
  • D.B. Clayson et al.

    Interspecies differences in response to chemical carcinogens

  • S.M. Cohen et al.

    Urothelial cytotoxicity and regeneration induced by dimethylarsinic acid in rats

    Toxicol. Sci.

    (2001)
  • L.M. Del Razo et al.

    Determination of trivalent methylated arsenic species in water, cultured rat hepatocytes, and human urine

    4th International Conference on Arsenic Exposure and Health Effects

    (2000)
  • EPA, 1981, Methane Arsonic Acid (MMA): 2-Year Chronic/Onogenic Rat Feeding Study. Memorandum from W. Dykstra,...
  • EPA, 1994, Carcinogenicity Peer Review of Cacodylic Acid. Memorandum from S. Malish and E. Rinde to C. Giles-Parker and...
  • C.H. Hsu et al.

    Mutational spectrum of p53 gene in arsenic-related skin cancers from the blackfoot disease endemic area of Taiwan

    Br. J. Cancer

    (1999)
  • J.S. Jones et al.

    The Saccharomyces cerevisiae RAD18 gene encodes a protein that contains potential zinc finger domains for nucleic acid binding and a putative nucleotide binding sequence

    Nucleic Acids Res.

    (1988)
  • K. Katakura et al.

    H DNA amplification in Leishmania resistant to both arsenite and methotrexate

    Mol. Biochem. Parisitol.

    (1989)
  • Cited by (702)

    View all citing articles on Scopus

    This manuscript has been reviewed in accordance with the policy of the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

    View full text