In the present study MRP2/ABCC2 and BSEP/ABCB11 expression were investigated in sandwich cultured (SC) human and rat hepatocytes exposed to the proinflammatory cytokines. The investigation was also done in lipopolysaccharide (LPS)-treated rats. In SC human hepatocytes, both absolute protein and mRNA levels of MRP2/ABCC2 were significantly downregulated by TNF-␣, IL-6, or IL-1␤. In contrast to mRNA decrease, which was observed for BSEP/ABCB11, the protein amount was significantly increased by IL-6 or IL-1␤. A discrepancy between the change in BSEP/ABCB11 mRNA and protein levels was encountered in SC human hepatocytes treated with proinflammatory cytokines. In SC rat hepatocytes, Mrp2/Abcc2 mRNA was down-regulated by TNF-␣ and IL-6, whereas the protein level was decreased by all three cytokines. Down-regulations of both Bsep/Abcb11 mRNA and protein levels were found in SC rat hepatocytes exposed to TNF-␣ or IL-1␤. Administration of LPS triggered the release of the proinflammatory cytokines and caused the decrease of Mrp2/Abcc2 and Bsep/ Abcb11 protein in liver at 24 h post-treatment; however, the Mrp2 and Bsep protein levels rebounded at 48 h post-LPS treatment. In total, our results indicate that proinflammatory cytokines regulate the expression of MRP2/Mrp2 and BSEP/Bsep and for the first time demonstrate the differential effects on BSEP/Bsep expression between SC human and rat hepatocytes. Furthermore, the agreement between transporter regulation in vitro in SC rat hepatocytes and in vivo in LPS-treated rats during the acute response phase demonstrates the utility of in vitro SC hepatocyte models for predicting in vivo effects.Drug transporters facilitate the passage of many drugs across cellular barriers during the process of absorption, distribution, metabolism, and elimination. The hepatobiliary excretion of drugs and drug metabolites is one of the primary elimination routes for endogenous and exogenous compounds from blood circulation (1). Multidrug resistance-associated protein 2 (MRP2/ABCC2) 4 and bile salt export pump (BSEP/ABCB11) are localized mainly on the canalicular membrane of hepatocytes and are responsible for elimination of conjugated bilirubin and bile acids as part of the hepatic detoxification process. The transporters are also simultaneously involved in hepatic excretion of diverse drugs and their metabolites into bile. Consequently, functional disruption of MRP2/ABCC25 and BSEP/ ABCB11 may result in drug-induced liver injury (2), which is a major cause of withdrawal of drugs from the market (3).Pharmacokinetics for numerous drugs has been reported to be significantly affected during inflammation (4). Proinflammatory cytokines, such as tumor necrosis factor-␣ (TNF-␣), interleukin-1␤ (IL-1␤) and IL-6 have been shown to regulate the expression of hepatic transporters during inflammation in rodents (5-8). Down-regulation of hepatic bile salt influx transporters such as the sodium-dependent taurocholate transporter (NTCP/SLC10A1) by inflammation has been characterized in both rodents and primary...

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ABSTRACT:Humanized mice that express the human UDP-glucuronosyltransferase (UGT) 1 locus have been developed in a Ugt1-null background as a model to improve predictions of human UGT1A-dependent drug clearance. Enzyme kinetic parameters (K m and V max ) and pharmacokinetic properties of three probe drugs were compared using wild-type and humanized UGT1 mice that express the Gilbert's UGT1A1*28 allele [Tg(UGT1

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A broad array of in vitro and in vivo assays has consistently demonstrated that glyphosate and glyphosate-containing herbicide formulations (GCHF) are not genotoxic. Occasionally, however, related and contradictory data are reported, including findings of mouse liver and kidney DNA adducts and damage following intraperitoneal (ip) injection. Mode-of-action investigations were therefore undertaken to determine the significance of these contradictory data while concurrently comparing results from ip and oral exposures. Exposure by ip injection indeed produced marked hepatic and renal toxicity, but oral administration did not. The results suggest that ip injection of GCHF may induce secondary effects mediated by local toxicity rather than genotoxicity. Furthermore, these results continue to support the conclusion that glyphosate and GCHF are not genotoxic under exposure conditions that are relevant to animals and humans.