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Title: Interspecies differences in metabolism of arsenic by cultured primary hepatocytes

Abstract

Biomethylation is the major pathway for the metabolism of inorganic arsenic (iAs) in many mammalian species, including the human. However, significant interspecies differences have been reported in the rate of in vivo metabolism of iAs and in yields of iAs metabolites found in urine. Liver is considered the primary site for the methylation of iAs and arsenic (+3 oxidation state) methyltransferase (As3mt) is the key enzyme in this pathway. Thus, the As3mt-catalyzed methylation of iAs in the liver determines in part the rate and the pattern of iAs metabolism in various species. We examined kinetics and concentration-response patterns for iAs methylation by cultured primary hepatocytes derived from human, rat, mice, dog, rabbit, and rhesus monkey. Hepatocytes were exposed to [{sup 73}As]arsenite (iAs{sup III}; 0.3, 0.9, 3.0, 9.0 or 30 nmol As/mg protein) for 24 h and radiolabeled metabolites were analyzed in cells and culture media. Hepatocytes from all six species methylated iAs{sup III} to methylarsenic (MAs) and dimethylarsenic (DMAs). Notably, dog, rat and monkey hepatocytes were considerably more efficient methylators of iAs{sup III} than mouse, rabbit or human hepatocytes. The low efficiency of mouse, rabbit and human hepatocytes to methylate iAs{sup III} was associated with inhibition of DMAs production bymore » moderate concentrations of iAs{sup III} and with retention of iAs and MAs in cells. No significant correlations were found between the rate of iAs methylation and the thioredoxin reductase activity or glutathione concentration, two factors that modulate the activity of recombinant As3mt. No associations between the rates of iAs methylation and As3mt protein structures were found for the six species examined. Immunoblot analyses indicate that the superior arsenic methylation capacities of dog, rat and monkey hepatocytes examined in this study may be associated with a higher As3mt expression. However, factors other than As3mt expression may also contribute to the interspecies differences in the hepatocyte capacity to methylate iAs.« less

Authors:
; ;  [1];  [2];  [1]
  1. Department of Nutrition, CB 7461, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States)
  2. Pharmacokinetics Branch, Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, 27711 (United States)
Publication Date:
OSTI Identifier:
21344946
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 245; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2010.01.015; PII: S0041-008X(10)00040-2; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ARSENIC; ARSENIC 73; DOGS; ENZYMES; GLUTATHIONE; KINETICS; LABELLING; LIVER; LIVER CELLS; MACACUS; MEN; METABOLISM; METABOLITES; METHYLATION; MICE; PROTEIN STRUCTURE; RABBITS; RATS; URINE; ANIMAL CELLS; ANIMALS; ARSENIC ISOTOPES; BETA DECAY RADIOISOTOPES; BIOLOGICAL MATERIALS; BIOLOGICAL WASTES; BODY; BODY FLUIDS; CHEMICAL REACTIONS; DAYS LIVING RADIOISOTOPES; DIGESTIVE SYSTEM; DRUGS; ELECTRON CAPTURE RADIOISOTOPES; ELEMENTS; GLANDS; INTERMEDIATE MASS NUCLEI; ISOTOPES; MALES; MAMMALS; MAN; MATERIALS; MONKEYS; NUCLEI; ODD-EVEN NUCLEI; ORGANIC COMPOUNDS; ORGANS; PEPTIDES; POLYPEPTIDES; PRIMATES; PROTEINS; RADIOISOTOPES; RADIOPROTECTIVE SUBSTANCES; RESPONSE MODIFYING FACTORS; RODENTS; SEMIMETALS; SOMATIC CELLS; VERTEBRATES; WASTES

Citation Formats

Drobna, Zuzana, Walton, Felecia S, Harmon, Anne W, Thomas, David J, Styblo, Miroslav, and Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-2774. Interspecies differences in metabolism of arsenic by cultured primary hepatocytes. United States: N. p., 2010. Web. doi:10.1016/j.taap.2010.01.015.
Drobna, Zuzana, Walton, Felecia S, Harmon, Anne W, Thomas, David J, Styblo, Miroslav, & Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-2774. Interspecies differences in metabolism of arsenic by cultured primary hepatocytes. United States. https://doi.org/10.1016/j.taap.2010.01.015
Drobna, Zuzana, Walton, Felecia S, Harmon, Anne W, Thomas, David J, Styblo, Miroslav, and Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-2774. 2010. "Interspecies differences in metabolism of arsenic by cultured primary hepatocytes". United States. https://doi.org/10.1016/j.taap.2010.01.015.
@article{osti_21344946,
title = {Interspecies differences in metabolism of arsenic by cultured primary hepatocytes},
author = {Drobna, Zuzana and Walton, Felecia S and Harmon, Anne W and Thomas, David J and Styblo, Miroslav and Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-2774},
abstractNote = {Biomethylation is the major pathway for the metabolism of inorganic arsenic (iAs) in many mammalian species, including the human. However, significant interspecies differences have been reported in the rate of in vivo metabolism of iAs and in yields of iAs metabolites found in urine. Liver is considered the primary site for the methylation of iAs and arsenic (+3 oxidation state) methyltransferase (As3mt) is the key enzyme in this pathway. Thus, the As3mt-catalyzed methylation of iAs in the liver determines in part the rate and the pattern of iAs metabolism in various species. We examined kinetics and concentration-response patterns for iAs methylation by cultured primary hepatocytes derived from human, rat, mice, dog, rabbit, and rhesus monkey. Hepatocytes were exposed to [{sup 73}As]arsenite (iAs{sup III}; 0.3, 0.9, 3.0, 9.0 or 30 nmol As/mg protein) for 24 h and radiolabeled metabolites were analyzed in cells and culture media. Hepatocytes from all six species methylated iAs{sup III} to methylarsenic (MAs) and dimethylarsenic (DMAs). Notably, dog, rat and monkey hepatocytes were considerably more efficient methylators of iAs{sup III} than mouse, rabbit or human hepatocytes. The low efficiency of mouse, rabbit and human hepatocytes to methylate iAs{sup III} was associated with inhibition of DMAs production by moderate concentrations of iAs{sup III} and with retention of iAs and MAs in cells. No significant correlations were found between the rate of iAs methylation and the thioredoxin reductase activity or glutathione concentration, two factors that modulate the activity of recombinant As3mt. No associations between the rates of iAs methylation and As3mt protein structures were found for the six species examined. Immunoblot analyses indicate that the superior arsenic methylation capacities of dog, rat and monkey hepatocytes examined in this study may be associated with a higher As3mt expression. However, factors other than As3mt expression may also contribute to the interspecies differences in the hepatocyte capacity to methylate iAs.},
doi = {10.1016/j.taap.2010.01.015},
url = {https://www.osti.gov/biblio/21344946}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 1,
volume = 245,
place = {United States},
year = {Sat May 15 00:00:00 EDT 2010},
month = {Sat May 15 00:00:00 EDT 2010}
}