ToxSci Advance Access published online on February 14, 2008
Toxicological Sciences, 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, CO 80523-1680, USA
Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand
School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan
Corresponding author: Dr. Raymond S. H. Yang, Quantitative and Computational Toxicology Group, Department of Environmental and Radiological Health Sciences, Colorado State University, 137A Physiology Building, Fort Collins, CO 80523-1680, USA, Phone: 1-970-491-5652, Fax: 1-970-491-7569, E-mail address: raymond.yang{at}colostate.edu
Received November 13, 2007; revision received January 22, 2008; accepted February 4, 2008
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Abstract |
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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 (AUCLiver) 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 Hirono et al (2005). 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