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  • Hepatic microsomal metabolic parameters are commonly used to

    2020-07-30

    Hepatic microsomal metabolic parameters are commonly used to understand and relate interspecies differences in susceptibility to a particular toxicant. In this regard, the CCl4 metabolic rate constants, Km of 56.8 μM and Vmax of 2.26 nmol/min/mg protein, for human liver microsomes varied less than 2-fold from values we measured (unpublished observations) in hepatic microsomes from untreated rats (Km of 59.1 μM and Vmax of 3.10 nmol/min/mg protein), mice (29.3 μM and 2.86 nmol/min/mg protein) and hamsters (30.2 μM and 4.1 nmol/min/mg protein). Therefore, these rodent species appear to make reasonable models for studying CCl4 metabolism and toxicity. In conclusion, these data suggest that CYP2E1 is the major human enzyme responsible for CCl4 bioactivation at lower, environmentally relevant levels. At higher CCl4 levels, CYP3A and possibly other CYP450 forms may contribute to CCl4 metabolism. Individual differences in CYP2E1 lobeline related to environmental, genetic or pathophysiological factors can therefore be expected to alter CCl4 metabolism and susceptibility to low-dose exposure to this agent.
    Acknowledgements We would like to thank Dr Ron Mason (NIEHS, Research Triangle Park, NC) for helpful discussion regarding the analysis of CCl4 metabolism, to Dr Karla Thrall and Dr Rick Corley (Battelle) for helpful discussions regarding study design and data interpretation, and to Jim Merdink and Karl Weitz (Battelle) for assistance in the analysis of chlorinated compounds by gas chromatography. Work performed by Pacific Northwest National Laboratory (PNNL) for Lovelace Respiratory Research Institute under Cooperative Agreement DE-FC04-96AL7604, Environmental Management Science Program, Office of Science and Technology, Office of Environmental Management, Department of Energy. PNNL is operated by Battelle for the US Department of Energy (DOE) under contract DE-ACO6-76RLO 1830. However, any opinions, findings, conclusions, or recommendations expressed herein are those of the authors and do not necessarily reflect the views of the DOE.
    Introduction Perfluorooctanesulfonate (PFOS) is a perfluorinated surfactant that has been used commercially in applications requiring exceptional stability and high surface tension reducing properties. Degradation of “precursor” compounds metabolically (Xu et al., 2004) or in the environment (D’Eon et al., 2006, Rhoads et al., 2008) may also lead to formation of PFOS. Quantitation of PFOS in biomonitoring samples from humans (Hansen et al., 2001) and wildlife (Giesy and Kannan, 2001) demonstrated broad dissemination in the environment, and, since that time, numerous environmental sampling and biomonitoring studies have confirmed the broad dissemination of PFOS in the environment (Butenhoff et al., 2006, Houde et al., 2006, Lau et al., 2007). Recent trend studies suggest that body burdens of PFOS in the general population have been in decline since circa 2000–2002 (Calafat et al., 2007, Olsen et al., 2008, Sundström et al., 2011), when the major United States manufacturer ceased production (Renner, 2001).