The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans
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).
References (87)
- et al.
Is the multidrug transporter a flippase?
Trends Biochem. Sci.
(1992) The barrier function of CYP3A4 and P-glycoprotein in the small bowel
Adv. Drug Deliv. Rev.
(1997)- et al.
The drug efflux-metabolism alliance: biochemical aspects
Adv. Drug Deliv. Rev.
(2001) - et al.
P-glycoprotein expression and function in circulating blood cells from normal volunteers
Blood
(1994) - et al.
Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver
Gastroenterology
(2001) - et al.
Genetic polymorphism in MDR-1: a tool for examining allelic expression in normal cells, unselected and drug-selected cell lines, and human tumors
Blood
(1998) - et al.
for the Swiss HIV Cohort Study, Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenentics study
Lancet
(2002) - et al.
Frequency of C3435T polymorphism of MDR1 gene in African people
Lancet
(2001) - et al.
Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice
Reprod. Toxicol.
(1998) - et al.
Interaction of drugs with P-glycoprotein in brain capillaries
Biochem. Pharmacol.
(1995)
Polarized transport of docetaxel and vinblastine mediated by P-glycoprotein in human intestinal epithelial cell monolayers
Biochem. Pharmacol.
The blood–brain barrier and oncology: new insights into function and modulation
Cancer Treat. Rev.
Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood–brain barrier and to increased sensitivity to drugs
Cell
Human P-glycoprotein transports cyclosporin A and FK506
J. Biol. Chem.
Human MDR1 and mouse mdr1a P-glycoprotein alter the cellular retention and disposition of erythromycin, but not of retinoic acid or benzo(a)pyrene
Arch. Biochem. Biophys.
In vitro and in vivo investigations on fluoroquinolones; effects of the P-glycoprotein efflux transporter on brain distribution of sparfloxacin
Eur. J. Pharm. Sci.
P-glycoprotein-mediated transcellular transport of MDR-reversing agents
FEBS Lett.
Effect of the P-glycoprotein inhibitor, SDZ PSC 833, on the blood and brain pharmacokinetics of colchicine
Life Sci.
Genomic organization of the human multidrug resistance (MDR1) gene and origin of P-glycoproteins
J. Biol. Chem.
Biochemistry of multidrug resistance mediated by the multidrug transporter
Annu. Rev. Biochem.
Biochemical, cellular, and pharmacological aspects of the multidrug transporter
Annu. Rev. Pharmacol. Toxicol.
From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance
Cell Mol. Life Sci.
Role of transport proteins in drug absorption, distribution and excretion
Xenobiotica
The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin
J. Clin. Invest.
Inhibition of P-glycoprotein-mediated drug transport: a unifying mechanism to explain the interaction between digoxin and quinidine
Circulation
Induction of P-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: a new type of drug/drug interaction
Clin. Pharmacol. Ther.
Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues
Proc. Natl. Acad. Sci. U.S.A.
Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood–brain barrier sites
Proc. Natl. Acad. Sci. U.S.A.
Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier
Proc. Natl. Acad. Sci. U.S.A.
Stage-specific distribution of P-glycoprotein in first-trimester and full-term human placenta
Histochem. J.
Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy
Mol. Carcinog.
Interrelationship between substrates and inhibitors of human CYP3A and P-glykoprotein
Pharm. Res.
OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine
Drug Metab. Dispos.
Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo
Proc. Natl. Acad. Sci. U.S.A.
Frequency of single nucleotide polymorphisms (SNPs) in the P-glycoprotein drug transporter MDR1 gene in Caucasians
Clin. Pharmacol. Ther.
Identification of functionally variant MDR1 alleles among European Americans and African Americans
Clin. Pharmacol. Ther.
Application of DHPLC to detect known and novel mutations in the MDR1 gene in different ethnicities
Pharmacol. Toxicol. (Abstract)
Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene
J. Pharmacol. Exp. Ther.
Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects
Clin. Pharmacol. Ther.
The C3435T mutation in the human MDR1 gene is associated with altered efflux of the P-glycoprotein substrate rhodamine 123 from CD56+ natural killer cells
Pharmacogenetics
MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects
Pharm. Res.
P-glycoprotein in the blood–brain barrier of mice influences the brain penetration and pharmacological activity of many drugs
J. Clin. Invest.
The predictive value of MDR1, CYP2C9, and CYP2C19 polymorphisms for phenytoin plasma levels
Pharmacogenomics
Cited by (242)
Making sense of norclozapine levels: 3 clinical axioms
2023, Schizophrenia ResearchThe effects of P-glycoprotein inhibitor zosuquidar on the sex and time-dependent pharmacokinetics of parenterally administered talinolol in mice
2021, European Journal of Pharmaceutical SciencesGenotypes and haplotypes of ABCB1 contribute to TAC chemotherapy response in Malaysian triple negative breast cancer patients
2018, Meta GeneCitation Excerpt :This result is concordant with other studies on breast, colorectal and prostate cancers (Andersen et al., 2013; Demidenko et al., 2015; Vaclavikova et al., 2009). It has been suggested that, in normal tissues it may act as a protective mechanism against noxious xenobiotics (Fromm, 2002). However, over-expression of ABCB1 mRNA was observed in patients who showed resistance to the chemotherapy, although the difference in expression level between patients who were resistant versus respond to treatment was statistically insignificant.
P-glycoprotein polymorphism and levothyroxine bioavailability in hypothyroid patients
2018, Saudi Pharmaceutical JournalABC-transporter blockage mediated by xanthotoxin and bergapten is the major pathway for chemosensitization of multidrug-resistant cancer cells
2017, Toxicology and Applied Pharmacology