Review Interrelationship between ATP-binding cassette transporters and oxysterols Jorge L.M. Ruiz, Lı ´via R. Fernandes, De ´ bora Levy, Se ´ rgio P. Bydlowski * Laboratory of Genetics and Molecular Hematology (LIM31), University of Sa˜o Paulo School of Medicine, Av. Dr. Ene ´as de Carvalho Aguiar, 155, 1st Floor, Room 43, 05403-000 Sa˜o Paulo/SP, Brazil 1. Introduction Oxysterols exhibit several biological activities, including the regulation of cholesterol homeostasis and cytotoxicity. Members of the ATP-binding cassette (ABC) transporter family have been implicated in a multitude of cell functions, including sterol homeostasis in a variety of tissues. Both oxysterols and ABC transporters mediate a number of cell signaling pathways that affect each other’s functions. This review addresses the mecha- nisms by which ABC transporters interact with cholesterol and oxysterols. 2. Oxysterols Oxysterols comprise a heterogeneous group of molecules derived from cholesterol through enzymatic and non-enzymatic oxidation (Fig. 1). Oxidation makes the molecules more hydro- philic, reduces their half-lives, and directs them to excretion or further oxidation [1]. Therefore, oxysterols can be considered a way to route the cholesterol molecule for catabolism. Hydroxyl, keto, hydroperoxy, epoxy, and carboxyl are the most common moieties derived from cholesterol oxidation [2]. 2.1. Enzymatic oxidation of cholesterol Some of the most physiologically important oxysterols are generated in cells by mitochondrial or endoplasmic reticulum cholesterol hydroxylases belonging to the cytochrome P450 (CYP) family. Several CYP enzymes participate in the conversion of cholesterol into particular hydroxycholesterols [3]. Cholesterol hydroxylase CYP3A4 produces 4b-hydroxycholesterol (4b-OHC) [4]. The hepatic enzyme cholesterol 7a-hydroxylase (CYP7A1) produces 7a-hydroxycholesterol (7a-OHC, also generated non- enzymatically) as the first committed step in the classical bile acid pathway; it is under strict metabolic control and multiple mechanisms are involved in its regulation [5]. Mitochondrial sterol 27-hydroxylase (CYP27A1) is expressed in several tissues, and is particularly high in the liver and macrophages. This enzyme catalyzes the first step in the alternative pathway for bile acid synthesis, producing 27-hydroxycholesterol (27-OHC), the major Biochemical Pharmacology 86 (2013) 80–88 A R T I C L E I N F O Article history: Received 23 January 2013 Accepted 27 February 2013 Available online 7 March 2013 Keywords: Oxysterols Cholesterol ABC transporters Cholesterol efflux Multiple drug resistance A B S T R A C T ATP-binding cassette (ABC) transporters constitute a ubiquitous superfamily of membrane proteins responsible for the translocation of several substances across membranes using the chemical energy provided by ATP hydrolysis. ABC transporters participate in many physiological and pathophysiological processes, including cholesterol and lipid transportation and multidrug resistance. Oxysterols are the products of cholesterol oxidation, formed by both enzymatic and non-enzymatic mechanisms. The role of oxysterols in cholesterol metabolism and several diseases has been widely investigated, but many questions remain to be answered. Several lines of evidence link ABC transporter functions with cholesterol and oxysterol metabolism. This review discusses ABC transporters, oxysterols, and how they interact with each other. ß 2013 Elsevier Inc. All rights reserved. Abbreviations: ABC, ATP-binding cassette; apo, apolipoprotein; BCRP, breast cancer resistance protein; CYP, cytochrome P450; EC, epoxycholesterol; ER, endoplasmic reticulum; GS-X, glutathione-conjugate; HDL, high-density lipoprotein; INSIG, insulin-inducible genes; 7-KC, 7-ketocholesterol; LDL, low-density lipoprotein; LDLr, LDL receptor; LXR, liver X receptor; MDR, multiple drug resistance; MOAT, multi-specific organic anion transporter; MRP, multidrug-related protein; OHC, hydroxycholesterol; ORP, OSBP-related protein; OSBP, oxysterol-binding protein; P-gp, P-glycoprotein; PXR, pregnane-X-receptor; RXR, retinoid X receptor; SCAP, SREBP cleavage activating protein; SREBP, sterol regulatory element binding protein. * Corresponding author at: Department of Hematology, University of Sa ˜o Paulo School of Medicine, Av. Dr. Ene ´as de Carvalho Aguiar, 155, 1st Floor, Room 43, 05403-000 Sa ˜o Paulo/SP, Brazil. Tel.: +55 11 3082 2398; fax: +55 11 3082 2398. E-mail addresses: jorgeruiz@usp.br (Jorge L.M. Ruiz), liviarosa@usp.br (L.R. Fernandes), deb.levy@lim31.fm.usp.br (D. Levy), spbydlow@usp.br, sergio.byd@lim31.fm.usp.br (S.P. Bydlowski). Contents lists available at SciVerse ScienceDirect Biochemical Pharmacology jo u rn al h om epag e: ww w.els evier.c o m/lo cat e/bio c hem p har m 0006-2952/$ – see front matter ß 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bcp.2013.02.033