title: Pharmacokinetics and effects on serum cholinesterase activities of organophosphorus pesticides acephate and chlorpyrifos in chimeric mice transplanted with human hepatocytes.
abstract: Organophosphorus pesticides acephate and chlorpyrifos in foods have potential to impact human health. The aim of the current study was to investigate the pharmacokinetics of acephate and chlorpyrifos orally administered at lowest-observed-adverse-effect-level doses in chimeric mice transplanted with human hepatocytes. Absorbed acephate and its metabolite methamidophos were detected in serum from wild type mice and chimeric mice orally administered 150mg/kg. Approximately 70% inhibition of cholinesterase was evident in plasma of chimeric mice with humanized liver (which have higher serum cholinesterase activities than wild type mice) 1day after oral administrations of acephate. Adjusted animal biomonitoring equivalents from chimeric mice studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Estimated plasma concentrations of acephate and chlorpyrifos in humans were consistent with reported concentrations. Acephate cleared similarly in humans and chimeric mice but accidental/incidental overdose levels of chlorpyrifos cleared (dependent on liver metabolism) more slowly from plasma in humans than it did in mice. The data presented here illustrate how chimeric mice transplanted with human hepatocytes in combination with a simple PBPK model can assist evaluations of toxicological potential of organophosphorus pesticides.
authors.affiliation: Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki 210-0821, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suemizu
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Sota
authors.affiliation: Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki 210-0821, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kuronuma
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan. Electronic address: hyamazak@ac.shoyaku.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
mesh_terms: D000818:Animals; D002678:Chimera / Q000097:blood* / Q000378:metabolism; D004390:Chlorpyrifos / Q000009:adverse effects / Q000493:pharmacokinetics*; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics; D002802:Cholinesterases / Q000097:blood* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009943:Organophosphorus Compounds / Q000009:adverse effects / Q000493:pharmacokinetics*; D009946:Organothiophosphorus Compounds / Q000009:adverse effects / Q000493:pharmacokinetics*; D010575:Pesticides / Q000009:adverse effects / Q000493:pharmacokinetics*; D063088:Phosphoramides / Q000009:adverse effects / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002800:Cholinesterase Inhibitors; D009943:Organophosphorus Compounds; D009946:Organothiophosphorus Compounds; D010575:Pesticides; D063088:Phosphoramides; C001969:acephate; C014655:methamidophos; D002802:Cholinesterases; D004390:Chlorpyrifos
keywords: Allometric scaling; Lowest-observed-adverse-effect level; Physiologically based pharmacokinetic model; Serum cholinesterase activities; Transplanted human liver cells