Interspecies differences in metabolism of arsenic by cultured primary hepatocytes

Journal Article · Sat May 15 00:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.01.015· OSTI ID:21344946

Drobna, Zuzana; Walton, Felecia S; Harmon, Anne W ^[1]; Thomas, David J ^[2]; Styblo, Miroslav ^[1]

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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)

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.

• OSTI ID: 21344946
• Journal Information: Toxicology and Applied Pharmacology, Vol. 245, 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.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

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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