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Recent advances in basic science
ABC of oral bioavailability: transporters as gatekeepers in the gut
  1. C G Dietrich1,
  2. A Geier2,
  3. R P J Oude Elferink3
  1. 1Department of Gastroenterology and Hepatology, Aachen University, Germany, and AMC Liver Centre, Academic Medical Centre, Amsterdam, the Netherlands
  2. 2Department of Gastroenterology and Hepatology, Aachen University, Germany
  3. 3AMC Liver Centre, Academic Medical Centre, Amsterdam, the Netherlands
  1. Correspondence to:
    Dr C G Dietrich
    Med Klinik III, Department of Gastroenterology and Hepatology, Pauwelsstr 30, 52057 Aachen, Germany; Christoph.Dietrichpost.rwth-aachen.de

https://doi.org/10.1136/gut.52.12.1788

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    MDR1 (ABCB1), MRP2 (ABCC2), and BCRP (ABCG2) are members of the family of ATP binding cassette (ABC) transporters. These are plasma membrane transporters that are expressed in various organs. The role of MDR1 and MRP2 in the hepatobiliary system is well defined; both contribute to bile formation by transport of drugs, toxins, and waste products across the canalicular membrane. As they transport exogenous and endogenous substances, they reduce the body load of potentially harmful compounds. The role of ABCG2, which is also expressed in the canalicular membrane of hepatocytes, has not yet been fully characterised. All three proteins are also expressed in the apical membrane of enterocytes where they probably control oral availability of many substances. This important “gatekeeper” function of ABC transporters has been recognised recently and is currently under further investigation. Expression and activity of these transporters in the gut may differ between individuals, due to genetic polymorphisms or pathological conditions. This will lead to individual differences in bioavailability of different drugs, toxins, and (food derived) carcinogens.

    Recent information on substrates, transport mechanisms, function, and regulation of expression of MDR1, MRP2, and BCRP in different species is summarised in this review.

    INTRODUCTION

    Detoxification of xenobiotics, including toxins, carcinogens, and drugs, is the central task of many metabolising enzymes in the body. Two groups of enzymes are known to handle metabolism of harmful compounds. The group of cytochrome P450 isoenzymes (CYPs) comprises numerous isoforms (approximately 60 are expected in humans1) leading to oxidation (mostly hydroxylation) of molecules (for an overview see Werck-Reichhart and Feyereisen2). Isoforms in the CYP groups 1, 2, and 3 mediate metabolism of many exogenous compounds. Many toxins and carcinogens require activation by CYP450 isoenzymes to obtain their reactive (that is, alkylating) properties in the body. Because CYP450 isoenzymes mostly catalyse the first step of …

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