Regulation of hepatic ABCC transporters by xenobiotics and in disease states

Abstract

The subfamily of ABCC transporters consists of 13 members in mammals, including the multidrug resistance-associated proteins (MRPs), sulfonylurea receptors (SURs), and the cystic fibrosis transmembrane conductance regulator (CFTR). These proteins play roles in chemical detoxification, disposition, and normal cell physiology. ABCC transporters are expressed differentially in the liver and are regulated at the transcription and translation level. Their expression and function are also controlled by post-translational modification and membrane-trafficking events. These processes are tightly regulated. Information about alterations in the expression of hepatobiliary ABCC transporters could provide important insights into the pathogenesis of diseases and disposition of xenobiotics. In this review, we describe the regulation of hepatic ABCC transporters in humans and rodents by a variety of xenobiotics, under disease states and in genetically modified animal models deficient in transcription factors, transporters, and cell-signaling molecules.

Simultaneous Absolute Protein Quantification of Transporters, Cytochromes P450, and UDP-Glucuronosyltransferases as a Novel Approach for the Characterization of Individual Human Liver: Comparison with mRNA Levels and Activities

“…Except for OATP1B1, protein and mRNA expression levels of the investigated transporters were not well correlated. This finding is in contrast to P450 enzymes and may be explained by the prominent role of post-transcriptional processes and intracellular trafficking in controlling the protein levels of transporters in the plasma membrane (Marinelli et al, 2005;Gu and Manautou, 2010). Therefore, mRNA expression cannot be considered as a suitable surrogate for expression levels of transmembrane pro- FIG.…”

The Blood-Testis Barrier and Its Implications for Male Contraception

“…Multidrug resistance-related proteins. MRP is another efflux transporter subfamily of the ABC transporter, consisting of MRP1 (ABCC1), MRP2 (ABCC2), and MRP3 (ABCC3), found in mammalian cells, as well as in plants and bacteria (Rappa et al, 1999;Pérez-Tomá s, 2006;Paumi et al, 2009;Gu and Manautou, 2010;Wanke and Kolukisaoglu, 2010). MRP1 was found to be expressed at relatively high levels in the mouse testis versus other organs.…”

Variations in ATP-Binding Cassette Transporter Regulation during the Progression of Human Nonalcoholic Fatty Liver Disease

“…The ABC family of transporters consists of a wide variety of proteins that hydrolyze ATP to actively transport xenobiotics, endobiotics, and conjugates across cellular membranes (Klaassen and Aleksunes, 2010) and include such members as the ABCC subfamily also known as multidrug resistanceassociated proteins, ABCB1 or P-glycoprotein, and ABCG2 or breast cancer resistance protein. Collectively, ABC transporters are large proteins possessing anywhere from 12 to 17 membrane-spanning regions, with the exception of ABCG2 (breast cancer resistance protein), which is considered a half-transporter (Gu and Manautou, 2010;Klaassen and Aleksunes, 2010). These efflux transporters reside on the sinusoidal and canalicular membranes of hepatocytes and are responsible for substrate transport into the blood and bile, respectively (Klaassen and Aleksunes, 2010).…”