Molecular processes in cellular arsenic metabolism.
Elucidating molecular processes that underlie accumulation, metabolism and binding of iAs and its methylated metabolites provides a basis for understanding the modes of action by which iAs acts as a toxin and a carcinogen. One approach to this problem is to construct a conceptual model that incorporates available information on molecular processes involved in the influx, metabolism, binding and efflux of arsenicals in cells. This conceptual model is initially conceived as a non-quantitative representation of critical molecular processes that can be used as a framework for experimental design and prediction. However, with refinement and incorporation of additional data, the conceptual model can be expressed in mathematical terms and should be useful for quantitative estimates of the kinetic and dynamic behavior of iAs and its methylated metabolites in cells. Development of a quantitative model will be facilitated by the availability of tools and techniques to manipulate molecular processes underlying transport of arsenicals across cell membranes or expression and activity of enzymes involved in methylation of arsenicals. This model of cellular metabolism might be integrated into more complex pharmacokinetic models for systemic metabolism of iAs and its methylated metabolites. It may also be useful in development of biologically based dose-response models describing the toxic and carcinogenic actions of arsenicals.
Thomas
David J
DJ
Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, 109 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA. thomas.david@epa.gov
D000818:Animals; D001151:Arsenic / Q000378:metabolism* / Q000493:pharmacokinetics; D001711:Biotransformation; D002477:Cells / Q000378:metabolism*; D006801:Humans; D011042:Poisons / Q000378:metabolism* / Q000493:pharmacokinetics
D011042:Poisons; D001151:Arsenic