Perfluoroalkyl substances (PFASs), including perfluoroalkyl carboxylates (PFCAs) and perfluoroalkyl sulfonates (PFSAs), are persistent amphiphilic chemicals many of which are distributed ubiquitously in the environment and can be frequently detected in human serum. High doses of certain PFAS cause toxicities in animal models. Renal clearance and hepatic accumulation of PFASs can vary among different species, between genders in the same species and are also influenced by the carbon chain length of the individual PFCAs. In general, PFASs with shorter-chain length are eliminated more efficiently through the kidney whereas the longer-chain length PFASs tend to accumulate in liver. Although there were extensive studies published over the past decade regarding toxicities of PFASs in animal models and potential health risks in humans, the molecular mechanisms responsible for PFAS’s disposition, such as the roles of specific transporters involved, have not been clearly addressed. Absorption, distribution and elimination of certain xenobiotics are largely influenced by transporters and recently published studies demonstrate that also PFCAs are substrates for several transporters. In order to further delineate the pharmacokinetic properties of the disposition of PFASs, the involvement of drug transporters expressed in liver, intestine and kidney was examined. In the first specific aim, I evaluated the hypothesis that drug transporters in the enterohepatic circulation contribute to the liver accumulation and long half-lives of long chain PFASs. To address this aim, uptake studies with perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS) using cells expressing liver transporters NTCP or OATPs as well as intestinal transporters ASBT, OATPs or OSTα/β were performed. The results demonstrated that human and rat NTCP, human OATP1B1, OATP1B3, OATP2B1, OSTα/β and rat OATP1A1, OATP1B2, OATP2B1, OATP1A5 can transport all three PFSAs, whereas, human ASBT can only transport PFOS. In addition, inhibition studies with human MRP2, BCRP and BSEP containing Sf9 vesicles suggested that these efflux transporters might be involved in the canalicular secretion of PFHxS and/or PFOS in the liver. In the second specific aim, I evaluated the hypothesis that the differences of renal clearance of PFASs among different species and genders are due to the differences of specific transporters expressed in the kidney. To address this aim, rat renal transporters OAT1, OAT3 and OATP1A1 were examined for the transport of PFBS, PFHxS and PFOS. The results show that the three PFSAs are substrates of rat OAT1, OAT3 and OATP1A1. In summary, this dissertation reveals that 1) drug transporters expressed in the liver and the intestine and involved in the enterohepatic circulation of bile acids contribute to the long halflives and the hepatic accumulation of PFHxS and PFOS in humans; 2) drug transporters in the liver, the intestine and the kidney contribute to species-, gender- and chain length-dependent elimination of PFASs.
|Advisor:||Hagenbuch, Bruno A.|
|Commitee:||Apte, Udayan, Blanco, Gustavo, Pritchard, Michele, Reed, Gregory|
|School:||University of Kansas|
|Department:||Pharmacology, Toxicology and Therapeutics|
|School Location:||United States -- Kansas|
|Source:||DAI-B 78/06(E), Dissertation Abstracts International|
|Subjects:||Toxicology, Surgery, Pharmacology|
|Keywords:||Drug transporters, Enterohepatic circulation, PFBS, PFHxS, PFOS, Perfluoroalkyl substances|
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