A possible role of multidrug resistance-associated protein 2 (Mrp2) in hepatic excretion of PCB126, an environmental contaminant: PBPK/PD modeling.
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.
Lohitnavy
Manupat
M
Quantitative and Computational Toxicology Group, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado 80523-1680, USA.
Lu
Yasong
Y
Lohitnavy
Ornrat
O
Chubb
Laura S
LS
Hirono
Shuichi
S
Yang
Raymond S H
RS
D000818:Animals; D003198:Computer Simulation; D004785:Environmental Pollutants / Q000493:pharmacokinetics*; D005260:Female; D008099:Liver / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D011078:Polychlorinated Biphenyls / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley
D004785:Environmental Pollutants; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011078:Polychlorinated Biphenyls; C023035:3,4,5,3',4'-pentachlorobiphenyl