ToxSci Advance Access originally published online on February 14, 2008
Toxicological Sciences 2008 104(1):27-39; doi:10.1093/toxsci/kfn026
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A Possible Role of Multidrug Resistance–Associated Protein 2 (Mrp2) in Hepatic Excretion of PCB126, an Environmental Contaminant: PBPK/PD Modeling
* Quantitative and Computational Toxicology Group, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado 80523-1680
Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand
School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan
1 To whom correspondence should be addressed at Quantitative and Computational Toxicology Group, Department of Environmental and Radiological Health Sciences, Colorado State University, 137A Physiology Building, Fort Collins, CO 80523-1680. Fax: (970) 491-7569. E-mail: raymond.yang{at}colostate.edu.
Received November 13, 2007; accepted February 4, 2008
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Abstract |
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3,3',4,4',5'-Pentachlorobiphenyl (PCB126) is a carcinogenic environmental pollutant and its toxicity is mediated through binding with aryl hydrocarbon receptor (AhR). Earlier, we found that PCB126 treated F344 rats had 110–400 times higher PCB126 concentration in the liver than in the fat. Protein binding was suspected to be a major factor for the high liver concentration of PCB126 despite its high lipophilicity. In this research, we conducted a combined pharmacokinetic/pharmacodynamic study in male F344 rats. In addition to blood and tissue pharmacokinetics, we use the development of hepatic preneoplastic foci (glutathione-S-transferase placental form [GSTP]) as a pharmacodynamic endpoint. Experimental data were utilized for building a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model. PBPK/PD modeling was consistent with the experimental PK and PD data. Salient features of this model include: (1) bindings between PCB126 and hepatic proteins, particularly the multidrug resistance–associated protein (Mrp2), a protein transporter; (2) Mrp2-mediated excretion; and (3) a relationship between area under the curve of PCB126 in the livers and % volume of GSTP foci. Mrp2 involvement in PCB126 pharmacokinetics is supported by computational chemistry calculation using a three-dimensional quantitative structure–activity relationship model of Mrp2 developed by S. Hirono et al. (2005, Pharm. Res. 22, 260–269). This work, for the first time, provided a plausible role of a versatile hepatic transporter for drugs, Mrp2, in the disposition of an important environmental pollutant, PCB126.
Key Words: carcinogenesis; disposition; physiologically based pharmacokinetics; polychlorinated biphenyls; PCB 126; Mrp2.