Human and Rat ABC Transporter Efflux of Bisphenol A and Bisphenol A Glucuronide: Interspecies Comparison and Implications for Pharmacokinetic Assessment

Abstract

Significant interspecies differences exist between human and rodent with respect to absorption, distribution, and excretion of bisphenol A (BPA) and its primary metabolite, BPA-glucuronide (BPA-G). ATP-Binding Cassette (ABC) transporter enzymes play important roles in these physiological processes, and their enzyme localization (apical vs. basolateral) in the plasma membrane allows for different cellular efflux pathways. In this study, we utilized an ATPase assay to evaluate BPA and BPA-G as potential substrates for the human and rat ABC transporters: P-glycoprotein (MDR1), multidrug resistance-associated proteins (MRPs), and breast cancer-resistant protein (BCRP). Based on high ATPase activity, BPA is likely a substrate for rat mdr1b but not for human MDR1 or rat mdr1a. Results indicate that BPA is a potential substrate for rat mrp2 and human MRP2, BCRP, and MRP3. The metabolite BPA-G demonstrated the highest apparent substrate binding affinity for rat mrp2 and human MRP3 but appeared to be a nonsubstrate or potential inhibitor for human MRP2, MDR1, and BCRP and for rat mdr1a, mdr1b, and bcrp. Analysis of ABC transporter amino acid sequences revealed key differences in putative binding site composition that may explain substrate specificity. Collectively, these results suggest that in both rat and human, apical transporters efflux BPA into the bile and/or intestinal lumen. BPA-G would follow a similar pathway in rat; however, in human, due to the basolateral location of MRP3, BPA-G would likely enter systemic and portal blood supplies. These differences between human and rodent ABC transporters may have significant implications for interspecies extrapolation used in risk assessment.

Biliary Elimination of Pemetrexed Is Dependent on Mrp2 in Rats: Potential Mechanism of Variable Response in Nonalcoholic Steatohepatitis

“…Although it may be that pemetrexed is an obligatory substrate for human MRP2, there have been instances of differential specificity between species, and total hepatic levels of MRP2/Mrp2 protein as well (Li et al, 2009). For instance, bisphenol-A glucuronide has distinct profiles in rodents and humans (Mazur et al, 2012). There are, however, precedents for Mrp2/Mrp3 studies of NASH completed in rodent MCD models that correlate to the human condition more reliably.…”

Generation and Characterization of a Breast Cancer Resistance Protein Humanized Mouse Model

“…Though the results obtained with topotecan might indicate a difference in the topotecan transport activity of mouse Bcrp versus human BCRP (see above), the systematic analysis of species differences by using the hBCRP mice is beyond the scope of this work and will be subject to further investigations. On the basis of previously published work, fumitremorgin C could be considered as a potential inhibitor (Gonzalez-Lobato et al, 2010) and pheophorbide A or bisphenol A as substrates (Li et al, 2008;Mazur et al, 2012) for such studies. Thus, the hBCRP mouse model provides a novel tool for identifying differences in inhibitor or substrate interactions with this transporter, either for basic research purposes or in drug development.…”

“…While most investigations have focused on the differences in the BCRP expression level between animals and man (Lai, 2009;Li et al, 2009;Warren et al, 2009;Uchida et al, 2011;Chu et al, 2013), a few studies have also reported species differences in BCRP substrate specificity or interaction with inhibitors (Li et al, 2008;Gonzalez-Lobato et al, 2010;Mazur et al, 2012). Although the amino-acid sequences between mouse Bcrp and human BCRP are 81% identical and 86% homologous and therefore relatively conserved (Doyle and Ross, 2003), these proteins vary in more than 90 amino acids.…”

MRP2 Inhibition by HIV Protease Inhibitors in Rat and Human Hepatocytes: A Quantitative Confocal Microscopy Study

“…Moreover, the difference in results between rat and human in the first place can be explained by a species difference in the amino acid sequence of the transporter. It was found that human MRP2 has 78% amino acid sequence identity with rat Mrp2 (Mazur et al, 2012). Moreover, a species difference in Mrp2/MRP2-mediated transport has been shown by several research teams.…”