| dc.contributor.author |
Mazur, CS |
en |
| dc.contributor.author |
Marchitti, SA |
en |
| dc.contributor.author |
Dimova, M |
en |
| dc.contributor.author |
Kenneke, JF |
en |
| dc.contributor.author |
Lumen, A |
en |
| dc.contributor.author |
Fisher, J |
en |
| dc.date.accessioned |
2014-06-06T06:51:50Z |
|
| dc.date.available |
2014-06-06T06:51:50Z |
|
| dc.date.issued |
2012 |
en |
| dc.identifier.issn |
10966080 |
en |
| dc.identifier.uri |
http://dx.doi.org/10.1093/toxsci/kfs167 |
en |
| dc.identifier.uri |
http://62.217.125.90/xmlui/handle/123456789/5728 |
|
| dc.subject |
Metabolism |
en |
| dc.subject |
Physiologically-based pharmacokinetics |
en |
| dc.subject |
Xenobiotic transporters |
en |
| dc.subject.other |
4,4' isopropylidenediphenol |
en |
| dc.subject.other |
ABC transporter |
en |
| dc.subject.other |
adenosine triphosphatase |
en |
| dc.subject.other |
bisphenol A glucuronide |
en |
| dc.subject.other |
breast cancer resistance protein |
en |
| dc.subject.other |
drug metabolite |
en |
| dc.subject.other |
multidrug resistance protein |
en |
| dc.subject.other |
multidrug resistance protein 1 |
en |
| dc.subject.other |
multidrug resistance protein 2 |
en |
| dc.subject.other |
multidrug resistance protein 3 |
en |
| dc.subject.other |
protein Mdr1a |
en |
| dc.subject.other |
protein Mdr1b |
en |
| dc.subject.other |
unclassified drug |
en |
| dc.subject.other |
amino acid sequence |
en |
| dc.subject.other |
apical membrane |
en |
| dc.subject.other |
article |
en |
| dc.subject.other |
basolateral membrane |
en |
| dc.subject.other |
bile |
en |
| dc.subject.other |
binding affinity |
en |
| dc.subject.other |
binding site |
en |
| dc.subject.other |
controlled study |
en |
| dc.subject.other |
enzyme activity |
en |
| dc.subject.other |
enzyme assay |
en |
| dc.subject.other |
enzyme specificity |
en |
| dc.subject.other |
enzyme substrate complex |
en |
| dc.subject.other |
human |
en |
| dc.subject.other |
intestine |
en |
| dc.subject.other |
metabolism |
en |
| dc.subject.other |
nonhuman |
en |
| dc.subject.other |
pharmacokinetics |
en |
| dc.subject.other |
portal vein blood |
en |
| dc.subject.other |
rat |
en |
| dc.subject.other |
risk assessment |
en |
| dc.subject.other |
species comparison |
en |
| dc.subject.other |
systemic circulation |
en |
| dc.subject.other |
Animals |
en |
| dc.subject.other |
ATP-Binding Cassette Transporters |
en |
| dc.subject.other |
Benzhydryl Compounds |
en |
| dc.subject.other |
Glucuronides |
en |
| dc.subject.other |
Humans |
en |
| dc.subject.other |
Phenols |
en |
| dc.subject.other |
Rats |
en |
| dc.subject.other |
Species Specificity |
en |
| dc.title |
Human and rat ABC transporter efflux of bisphenol A and bisphenol A glucuronide: Interspecies comparison and implications for pharmacokinetic assessment |
en |
| heal.type |
journalArticle |
en |
| heal.identifier.primary |
10.1093/toxsci/kfs167 |
en |
| heal.publicationDate |
2012 |
en |
| heal.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. Published by Oxford University Press 2012. |
en |
| heal.journalName |
Toxicological Sciences |
en |
| dc.identifier.issue |
2 |
en |
| dc.identifier.volume |
128 |
en |
| dc.identifier.doi |
10.1093/toxsci/kfs167 |
en |
| dc.identifier.spage |
317 |
en |
| dc.identifier.epage |
325 |
en |