ABC of oral bioavailability: transporters as gatekeepers in the gut

Abstract

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.

Figure 1

Determinants of oral bioavailability. Although transporters are only present in the intestine and liver, they influence almost all parameters of bioavailability (the large arrows indicate changes in the respective parameter in the absence of transporters). Effects can vary depending on the substrate and respective transporter. The importance of the kidney in systemic excretion of xenobiotics is mainly confined to glomerular filtration while active transporter mediated tubular secretion probably plays only a minor role.

Figure 2

Expression levels of transporters in different parts of the intestine and the liver (see text for details).

Figure 3

Scheme of the rat Mrp2 promoter, showing overlapping binding sites for different nuclear receptors, which activate transcription. ER8 and DR5 denote the respective binding sites (see text for abbreviations of the nuclear receptors). HNF, hepatocyte nuclear factor. Note that several different heterodimers can bind to the ER8 element. Binding of different receptors to their respective binding site at the same time can result in complex regulation events.

Figure 4

Schematic representation of the defence system in enterocytes. The different lines of defence are further explained in the text. Note that nuclear receptors as common activators can upregulate enzymes of all metabolic steps. CYP, cytochrome P450; UGT, UDP-glucuronosyltransferases; SULT, sulphotransferases;+, upregulation, ?, unknown effect.