A Possible Role of Multidrug Resistance–Associated Protein 2 (Mrp2) in Hepatic Excretion of PCB126, an Environmental Contaminant: PBPK/PD Modeling

Abstract

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.