Elsevier

Advanced Drug Delivery Reviews

Volume 54, Issue 10, 18 November 2002, Pages 1295-1310
Advanced Drug Delivery Reviews

The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans

https://doi.org/10.1016/S0169-409X(02)00064-9Get rights and content

Abstract

The MDR1 (ABCB1) gene product P-glycoprotein is a membrane protein, which functions as an ATP-dependent exporter of xenobiotics from cells. Its importance was first recognized because of its role in the development of multidrug resistance (MDR) of cultured tumor cells against various anticancer agents. It is now, however, well established that this transporter is not only expressed in tumor cells, but also in normal tissues with excretory function (intestine, liver, kidney). Since P-glycoprotein has a very broad substrate specificity, it determines disposition of a broad variety of drugs. Moreover, induction and inhibition of P-glycoprotein are new mechanisms for drug interactions in humans. Very recently, systematic screens of the MDR1 gene have identified multiple single nucleotide polymorphisms. Some of those appear to be associated with altered transporter function and expression. This review discusses the currently available data on the influence of MDR1 polymorphisms on P-glycoprotein tissue expression, drug disposition, treatment outcome and disease risk.

Introduction

The MDR1 gene is located on chromosome 7 and consists of 28 exons. The 1280 amino acid protein has two homologous halves, each containing six transmembrane domains and an ATP-binding site. Since P-glycoprotein appears to detect and eject its substrates before they reach the cytoplasm, it has been suggested that it acts as a ‘hydrophobic vacuum cleaner’ or a flippase, which removes its substrates from the lipid bilayer [1], [2]. Excellent reviews on P-glycoprotein structure–function relationships were recently published [3], [4]. It is now well established that P-glycoprotein plays an important role in drug disposition, in particular due to its co-localization with the major drug metabolizing enzyme CYP3A4 in the small intestine and liver [5], [6], [7]. P-glycoprotein is thought to function as a protective mechanism against xenobiotics, which limits absorption from the GI tract and promotes efflux of these compounds into bile and urine. Moreover, P-glycoprotein provides additional protection for the brain, testis or fetus due to its expression in the respective blood–tissue barriers. In vitro and in vivo studies both revealed inhibition and induction of P-glycoprotein as new mechanisms underlying drug interactions [8], [9], [10]. Recently, multiple MDR1 polymorphisms have been identified. This review summarizes the currently available data on the potential effect of MDR1 polymorphisms on P-glycoprotein expression in normal tissues, its consequences for drug disposition, drug efficacy and disease risk.

Section snippets

P-glycoprotein tissue distribution

P-glycoprotein is not only expressed in tumor cells, but also in cells of several normal tissues. In liver it was detected on the biliary canalicular surface of hepatocytes and the apical surface of small biliary ductules. In the small intestine and colon, it is localized on the apical surface of columnar epithelial cells, and in kidneys it is found on the brush border membrane of proximal tubules. Moreover, it is detectable on the apical surface of small ductules in the pancreas and on the

P-glycoprotein substrates

P-glycoprotein has a very broad substrate specificity and transports many structurally unrelated compounds. These substances are usually hydrophobic and amphipathic. Table 2 provides a summary of drugs, which are substrates of P-glycoprotein. In addition to anticancer agents, this transporter translocates cardiac drugs, HIV protease inhibitors, immunosuppressants, antibiotics, β-adrenoceptor antagonists and antihistamines. The majority of P-glycoprotein substrates and inhibitors also interact

MDR1 polymorphisms and P-glycoprotein expression and function

In recent years, more than 20 single nucleotide polymorphisms have been identified in the MDR1 gene. A summary of these polymorphisms including genotype and allotype frequencies are summarized in Table 3. Further details on interethnic differences in MDR1 variants are given in Section 8. The first mutations in normal cells were described by Mickley et al. (G2677T, G2995A; [20]). A first systematic screen of the MDR1 gene was conducted by Hoffmeyer et al. [21], who analyzed all 28 exons of the MDR1

MDR1 polymorphisms and drug disposition

The currently available data on the influence of MDR1 polymorphisms on drug disposition are summarized in Table 5. Hoffmeyer et al. [21] reported in accordance with the reported lower intestinal P-glycoprotein expression in the 3435TT group, higher maximal digoxin plasma concentrations during steady-state in the TT group in comparison to subjects with the CC genotype (Fig. 1B). In accordance with their own data on MDR1 mRNA expression [26] (and in contrast to findings by Hoffmeyer et al. [21]),

MDR1 polymorphisms and treatment outcome

So far, little information is available regarding the potential importance of MDR1 polymorphisms on treatment outcome. The highly interesting observation of MDR1 genotype-dependent treatment outcome of HIV infection during antiretroviral therapy has been discussed in the previous section.

P-glycoprotein is an essential part of the blood–brain barrier and limits drug permeability into the CNS. P-glycoprotein substrates (e.g. doxorubicin, vincristine, etoposide) are used in standardized treatment

MDR1 polymorphisms and disease risk

Parkinson’s disease is a neurodegenerative disorder of unknown etiology. Epidemiological data suggest that both genetic and environmental factors play a role for disease risk. It was speculated that low P-glycoprotein expression in the blood–brain-barrier may result in a less efficient protection of the CNS from neurotoxic xenobiotics and an increased risk for the development of Parkinson’s disease. Indeed, preliminary data indicate that the frequency of MDR1 3435 TT individuals was highest in

Interethnic differences of MDR1 polymorphisms

Recent studies indicate that the 3435C allele is considerably more frequent in African populations in comparison to Caucasian and Asian populations (Fig. 4, [23], [51], [52]). The interethnic differences observed for the C3435T polymorphism are summarized in Table 6. One could speculate that the higher frequency of the CC genotype observed in Africans as compared to the Caucasian and Asian populations results from a selective advantage offered by this genotype against gastrointestinal tract

Conclusion

During recent years, considerable progress has been made in the understanding of transporter-mediated active uptake and efflux processes for drug disposition. The role of the MDR1 gene product P-glycoprotein for drug disposition and drug effects has clearly been demonstrated. The recent identification of multiple single nucleotide polymorphisms in the MDR1 gene provided an important basis for studies on the impact of these mutations on P-glycoprotein function both in vitro and in vivo. Although

Acknowledgements

I would like to thank Dr. L. Becquemont and Dr. O. Burk for valuable comments to this manuscript. Our own work cited is supported by grants of the Deutsche Forschungsgemeinschaft (FR 1298/2-1; Bonn, Germany) and the Robert Bosch Foundation (Stuttgart, Germany).

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