MDR1基因多态性及其临床相关性研究进展

遗 传 学 报 Acta Genetica Sinica , February 2006, 33 (2)：93–104 ISSN 0379-4172

MDR 1 Gene Polymorphisms and Clinical Relevance

LI Yan-Hong 1, WANG Yong-Hua 1, LI Yan 2, YANG Ling 1,①

1. Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China ;

2. School of Chemical Engineering, Dalian University of Technology, Dalian 116012, China

Abstract: In vivo and in vitro studies have demonstrated that P-glycoprotein (P-gp) plays a very significant role in the ADME processes (absorption, distribution, metabolism, excretion) and drug-drug interaction (DDI) of drugs in humans. P-gp is the product of multidrug resistance gene (MDR 1/ABCB 1). Pharmacogenomics and pharmacogenetics studies have revealed that genetic poly-morphisms of MDR 1 are associated with alteration in P-gp expression and function in different ethnicities and subjects. By now, 50 single nucleotide polymorphisms (SNPs) and 3 insertion/deletion polymorphisms have been found in the MDR 1 gene. Some of them, such as C3435T, have been identified to be a risk factor for numerous diseases. It is believed that further understanding of the physiology and biochemistry of P-gp with respect to its genetic variations may be important for individualized pharmacotherapy. Therefore, based on the latest public information and our studies, this review focuses on the following four aspects: 1) the impact of P-gp on pharmacokinetics; 2) MDR 1 genetic polymorphisms and their impacts on pharmacogenetics; 3) relationship between al-tered P-gp expression and function and the MDR 1C3435T SNP, and 4) relevance of MDR 1 polymorphisms to certain human diseases. Key words: P-glycoprotein (P-gp); MDR 1; genetic polymorphism; pharmacogenetics

Received: 2005-06-02; Accepted: 2005-09-12

This work was supported by the 973 Program (No.2003CCA03400) and the 863 Program (No.2003AA223061) of Ministry of Sci-ence and Technology of China.

① Corresponding author. E-mail: yling@https://www.sodocs.net/doc/1c19107308.html,

Recent years have seen a rapidly growing col-lection of articles on the topic of P-glycoprotein (P-gp) [1-3]. P-gp, a pivotal member of ATP-binding cassette (ABC) transporters, is an energy-dependent efflux pump. In vitro and in vivo studies have dem-onstrated that P-gp plays a very important role in the ADME processes (absorption, distribution, metabo-lism, excretion) of a wide variety of drugs, and is also involved in the drug-drug interaction (DDI) in humans [4]. P-gp, the product of multidrug resistance gene (MDR 1/ABCB 1), was first described as a 170 kDa protein abundantly expressed in Chinese hamster ovary (CHO) cells in 1976 [5]. A lot of pharmacoge-nomics and pharmacogenetics studies have revealed that some SNPs of the MDR 1 gene are associated with alteration in P-gp expression and function among different ethnicities and subjects [6-8]. With the development of the technology for individualized pharmacotherapy, a timely review of the current state of knowledge on the genetic polymorphisms of MDR 1 would be important. Therefore, this article focuses on the latest information of the human drug transporter P-gp and genetic polymorphisms of MDR 1, including the pharmacogenetics of MDR 1 and its impact on P-gp expression and function, and the association of MDR 1 polymorphisms with human diseases.

1 The Product of MDR 1 Gene: P-glycoprotein

A lot of ABC-transporter genes and proteins have been identified in the past 30 years. ABC trans-porter is a protein superfamily, whose members are characterized by two highly conserved ATP binding cassettes. In all, 48 different members, forming 8 dif-ferent subfamilies (A-G) based on sequence similari-

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ties, have been identified in the human genomes［9-12］. The ABC superfamily of proteins can transport a wide range of substances, such as ions, sugars, gly-cans, phospholipids, amino acids, peptides, proteins, drugs, and toxins [12].

Within the ABC superfamily, P-gp appears to be the most important for the disposition of xenobiotics in the human body. It is called a “traffic ATPases” that is involved in the extrusion of amphoteric com-pounds [13,14]. In normal tissues, it is expressed in ex-cretory organs, such as the intestines, liver, kidneys and may act as a protective mechanism against nox-ious xenobiotics[15-19]. High levels of P-gp expression may result in a decrease in intracellular drug concen-tration. P-gp is overexpressed in neoplastic cells, a fact that is related to worse treatment outcome and prognosis in a number of tumors, e.g. acute myeloid leukemia[20]. Moreover, P-gp could defend against viral infections, especially in the cellular uptake of viral particles and virus production[21]. The expres-sion level and functional integrity of P-gp may affect its pharmacogenetics and its interaction with drugs. Therefore, it plays an important role in drug efficacy and toxicity during treatment.

2 The Impact of P-gp on Pharmacokinetics

P-gp could interact with a broad spectrum of structurally-unrelated substrates, from vinca alkaloids, calcium channel blockers, anthracyclines, taxol, an-tiarrhythmics, epipodophyllotoxins, antihypertensives, antibiotics, β-adrenoceptor antagonists, immunosup-pressants, cytotoxic agents and steroid hormones to HIV protease inhibitors[22]. Moreover, the most puz-zling feature of P-gp is that it is not successful to predict P-gp-mediated transport of a substance from its chemical structure[23,24]. It is well known that many substrates of P-gp have been shown to be potent P-gp inhibitors, including channel blockers, calmodulin antagonists, immunosuppressants, and protein kinase inhibitors[25].

The level of P-gp activity may determine tissue distribution of drugs, affect uptake from the gastrointes-tinal tract as well as elimination into urine or bile [26]. In clinical studies it was found that co-administration of P-gp substrate digoxin with the P-gp inhibitor quinidine increased digoxin serum concentration in humans[27]. Moreover, rifampin, one of the well-known P-gp substrates, can induce P-gp and results in de-creased plasma concentrations of its substrates, e.g. digoxin and talinolol [28]. It is assumed that this is caused by modification of P-gp function with co-administered drugs. The potential importance of this phenomenon can be easily understood as DDI among various commonly used medications with in the spectrum of P-gp substrates. Furthermore, the major drug-metabolizing enzymes in humans, i.e. cytochrome P450s (e.g. CYP3A4), also share a sig-nificant overlap in substrate specificity with P-gp, making it more difficult to study the pharmacokinet-ics of P-gp[7]. Therefore, the influence of P-gp on pharmacokinetics is gaining attention.

3 Genetic Polymorphisms of MDR1

MDR1, located on chromosome 7q21.1, is com-posed of 28 exons and can encode a protein of 1 280 amino acids[9-12]. Mutational analyses have revealed that the MDR1 gene is highly polymorphic and it is extensively used to investigate P-gp structure-function relationships. The first systematic SNP screening of the MDR1 gene revealed 15 different exonic and intronic SNPs in a healthy Caucasian population[6]. Moreover, a total of 50 SNPs and 3 insertion/deletion polymor-phisms have been reported in the MDR1 gene in re-cent years [10]. Among them, it appears that re-searchers are more interested in only 28 SNPs at 27 positions[10,24,30-36]. All 28 exons, including the core promoter region and exon-intron boundaries ranging from 49 to 587 bp, were sequenced using specific oligonucleotide primers derived from the original “wild-type” MDR1 sequence (GenBank Accession No. AC002457 or AC005068). Fig.1 shows the sec-ondary structure of P-gp and the positions of some important SNPs in the human MDR1 gene, which may affect the MDR1 coding sequence.

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Table 1 Genetic polymorphisms in MDR 1 Position Location Effect

T-129C(T12C) Exon

1a Non-coding C-4T Exon 1b Non-coding G-1A Exon 2 Non-coding A61G Exon 2 Non-coding G5/-25T Exon 2 Asn21Asp G5/-35C Intron T307C Intron

C6/+139C Exon

5 Phe103Leu A548G Intron G1199A Exon 7 Asn183Ser C1236T Exon 11 Ser400Asn C12/+44T Exon 12 Wobble(Gly412Gly)C1474T Intron

T17/-76A Exon

13 Arg492Cys A17/+137G Intron

C2650T Intron G2677T Exon 21 Wobble(Leu884Leu)A2956G Exon 21 Ala893Thr G2995A Exon 21 Ala893Ser A3320C Exon 24 Met986Val

C3396T Exon 24 Ala999Thr T3421A Exon

26 Gln1107Pro C3435T Exon 26 Wobble T3421A Exon 26 Ser1141Thr C3435T Exon 26 Wobble(Ile1145Ile) G4030C Exon 28 Silent A4036G Exon 26 Silent

Some of the polymorphisms in the MDR 1 gene are ‘silent’, and cause no amino-acid changes (e.g. C1236T, C3396T and C3435T). However, some are found to change an amino acid (e.g. A61G , G1199A, A2956G , T3421A). Interestingly, among the SNPs reported previously that result in amino acid changes, some of them encode amino acids located in the trans-membrance domain of P-gp (e.g. A2956G in exon 24), and several are very close to the A TP-binding site (e.g. G1199A in exon 11). Seven synonymous mutations are at A1a/-41G , G5/-25T, G5/-35C, C6/+139C, C12/+44T, T17/-76A, A17/+137G , which are all located in introns. Four SNPs are at wobble positions with no amino acid changes [C1236T (exon 12), C2650T (exon 21) and C3435T, C3396T (both in exon26)]. Subsequently, a screen of 461 German Caucasians for allele and genotype distribution further revealed two rare mutations (G2677A: Ala893Thr; and A3320C: Gln1107Pro) [37]. Additional mutations were identi-fied in Asians including 5′-flanking A-41G , C-145G (exon 1a)[38], as well as three nonsynonymous mu-tations (A548G: Asn183Ser; C1474T: Arg492Cys; and T3421A: Ser1141Thr) in different ethnic populations [8]. Table 1 summarizes some of the exonic and intronic polymorphisms identified up to now (more detailed information is referenced https://www.sodocs.net/doc/1c19107308.html,/SNP/snp_ref.cgi?locu sId=5243).

In recent years, most of the MDR 1 SNPs were identified, with some resulting in changes in P-gp ex-pression and function [6,18,19,35]. The A61G mutation (Asn21Asp) may contribute to a net charge change (basic to acidic) close to the N-terminus of P-gp, which appears to be of minor functional importance [39]. Fur-thermore, T-129C, a noncoding mutation located within the promoter (exon 1b), has been found to lower P-gp expression by two-folds in human pla-centa [18]. The amino acid alteration Phe103Leu at T307C (exon 5) is located next to the second trans-membrance domain on the extracellular side of P-gp. The change from a large aromatic to a large lipophilic residue results in a structural alteration of P-gp. The

Fig. 1 Schematic representation of P-gp secondary structure and the positions of some important polymorphisms in the human MDR 1 gene

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nonsynonymous G1199A (Ser400Asn) in exon 11 brings about a significant size change, and depending on the pH and isoelectric environment of the residue, may lead to a charge change in the protein. This SNP is located on the cytoplasmic side just ahead of the first ATP-binding domain[29]. C1236T in exon 12, the synonymous polymorphism, is one of the SNPs with the highest frequencies[40]. G2677T/A, a missense mutation in exon 21 that results in an amino acid change from Ala 893 to Ser or Thr, has also been as-sociated with altered P-gp expression[18,41]. Another polymorphism, G2995A in exon 24 changes Ala 999 to Thr in the second transmembrance domain closer to the ATP-binding domain[36]. Finally, MDR1C3435T is another wobble mutation that doesn’t alter the amino acid Ile at the position 1145. The potential functional significance of these polymorphisms can be deduced by pinpointing them on the domain structure of P-gp.

Six MDR1 cDNAs with different SNPs, which were 2677G/3435T, 2677A/3435C, 2677A/3435T, 2677T/3435C, 2677T/3435T and the wild-type 2677G/3435C,were expressed in LLC-PK1 cells. P-gp transcellular transport activities and intracellular accumulation were determined using four structurally diverse compounds: verapamil, digoxin, vinblastine and cyclosporin A. However, no significant difference was observed in P-gp activity among different cells expressing six types of MDR1 cDNAs. Therefore, the author thought that two frequently observed MDR1 SNPs (G2677T/A, C3435T) had no effect on the P-gp activities expressed in LLC-PK1 cells in vitro, and that other genetic or environmental factors might control the MDR1 expression and activity in vivo[42]. Furthermore, Kimchi-Sarfaty and his colleagues car-ried out a study to characterize the functional conse-quences of five coding SNPs (Asn21Asp, Phe103Leu, Ser400Asn, Ala893Ser, Ala999Thr) using a vaccinia virus-based transient expression system, but it was found that the distribution and function of P-gp in the cells were similar to wild-type P-gp in the human body[43]. The mechanism of these contradictory re-sults regarding the G2677T/A and C3435T polymor-phisms function is unclear until now. 4 MDR1C3435T Genotype-Related P-gp

Expression and Function in Humans

4. 1 The MDR1C3435T genotypes

Among the 50 SNPs of the MDR1 gene, more attention has been focused on mutation at position 3435 in exon 26 (C3435T), which is the only silent polymorphism identified so far that might influence P-gp expression in different human tissues and dif-ferent races. Hoffmeyer et al.[6] showed that homo-zygous T-allele (TT) was associated with more than two-fold lower intestinal MDR1 expression levels compared with homozygous CC samples. Subjects with the TT genotype had on average a significantly (1.5-fold) lower P-gp expression compared to the CC genotype group (P=0.0065) [44]. The mean placental P-gp expression level in heterozygous (CT) samples was 2-fold lower than that in homozygous (TT) sam-ples [18].

Accordingly, subjects with the TT genotype had higher steady-state plasma concentration of digoxin after oral administration than wild-type subjects [6]. Moreover, a significant correlation was observed be-tween the C3435T SNP and digoxin AUC (P<0.05). Homozygous TT subjects had 20% higher digoxin plasma concentrations than CT subjects, and CC sub-jects had a trend for higher 48 h digoxin urinary re-coveries (TT>CT>CC) [45]. Homozygous CC subjects had a more pronounced efflux of rhodamine from CD56+ natural killer cells and a higher leukocyte MDR1 mRNA expression than subjects with the TT genotype. Reduced P-gp activity was also found in natural killer cells from healthy individuals having the TT genotype in comparison with wild-type sub-jects (the homozygous CC genotype) [46]. Moreover, P-gp function was significantly decreased in CD56+ cells in the TT group compared with the CC group (rhodamine fluorescence CC vs TT: 45.6±7.2% vs 61.1±12.3%, P<0.05; CI 95%) [47]. In the most re-cent report, it was believed that the effect of MDR1 G2677T/C3435T haplotypes on fexofenadine dispo-sition was magnified in the presence of itraconazole (a P-gp inhibitor). In addition, the G2677A/C3435C

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Table 2 Observed genotype and allele frequencies of the MDR 1 exon 26 C3435T polymorphisms in populations of different ethnicities Allele frequencies

Genotype frequencies

Population studied C T CC CT

TT

References

Chinese (n = 265) 0.56 0.44 0.32 0.48 0.20 Not published German (n = 188) 0.52 0.48 0.27 0.48 0.24 [6] Ashkenazi (n = 100) 0.65 0.35 0.42 0.46 0.12 [55] French (n = 81)

0.57 0.43 0.36 0. 42 0.22 [58] Caucasian (UK) (n = 190) 0.48 0.42 0.24 0.48 0.28 [8] Spanish (n = 408) 0.52 0.48 0.26 0.52 0.22 [60] Polish (n = 122)

0.62 0.38 0.42 0.41 0.17 [59] New Zealander (n = 160) 0.47 0.53 0.21 0.52 0.27 [54] Ghanaian (n = 206) 0.83 0.17 0.67 0.34 0.00 [8] Kenyan (n = 80) 0.83 0.17 0.70 0.26 0.04 [8] Sudanese (n = 51) 0.73 0.27 0.52 0.43 0.06 [8] Filipino (n = 60) 0.56 0.41 0.38 0.42 0.20 [8] Saudi (n = 96) 0.55 0.45 0.37 0.38 0.26 [8] Japanese (n = 114) 0.61 0.39 0.35 0.53 0.12 [61] Malay (n = 99) 0.48 0.52 0.25 0.46 0.28 [56] Indian (n = 264 )

0.38 0.62 0.25 0.46 0.28 [56]

haplotypes may help improve the predictability of MDR 1 genetic polymorphism for MDR 1 functional changes [48]. However, the relationship between the MDR 1 SNP genotypes and the disposition of some P-gp substrates is not completely clear.

4. 2 Distribution of the MDR 1C3435T genotypes It has been found that the distribution of C3435T polymorphism is significantly influenced by ethnicity [8]

. Large-scale genotyping studies of MDR 1C3435T polymorphism have been carried out in different eth-nic populations: German [46,47,49,50], American [6-8] (including Europe American and African American), Japanese [18,51,52], Korean [53], New Zealander [54], Jew [55] as well as in some African [8] and Asian [56]. The comparisons of MDR 1C3435T genotyping analysis within different ethnicities are presented in Table 2. In our study (not published), the frequency of the C allele was 0.56, which was similar to the Asia/Europe population (C = 0.38–0.62), but was much lower than African populations (C =0.73–0.83). Statistical analy-sis revealed a significant difference in C allele fre-quencies of the MDR 1C3435T between Chinese and African (Ghanaian, Kenyan and Sudanese) popula-

tions (P <0.001) [8]. Moreover, there was also a dif-ference between Chinese and New Zealander. This study shows that the mutant T allele is relatively rare in African ancestry populations, but exists at higher frequencies in Chinese Han populations. The TT genotype was not detected in the 206 Ghanaians studied, but accounted for 20%, 24% and 28% in subjects from China, Germany, UK, respectively. However, the frequency of the C allele was not sig-nificantly different between the European (Germany, France, Polish and Spanish) [57-60] and Asian (Philip-pines, Saudi Arabia, Malaysia, India and Japan) [8,56,61]. The difference in polymorphic allele frequency be-tween West Africans and African Americans popula-tions has also been observed [7]. Those results suggest that evaluation of MDR 1C3435T polymorphism is of great importance for individualized pharmacotherapy. 4. 3 MDR1 mRNA expression

Based on the level of MDR 1 mRNA expression in peripheral blood mononuclear cells (PBMC), two independent studies confirmed an association toward lower values in 3435TT subjects as compared to higher levels in individuals with the CT and CC

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genotypes [46,50]. These findings confirmed that sub-jects homozygous for TT showed 42% lower mRNA expression levels than subjects homozygous for CC (0.7±0.6 vs 1.2±1.1, CI 95%) [46]. Moreover, mRNA quantification in duodenal enterocytes from 13 healthy Japanese individuals showed higher mean expression levels of MDR1 mRNA in homozygous carriers for 3435TT than subjects with a CT or CC genotype [62]. More recently, it was reported that the abundant 3435C>T SNP appears to be a main factor in allelic variation of MDR1 mRNA expression in the liver [53]. However, those data are in contrast to the following study: the genetic polymorphisms, G2677T in exon 21 and C3435T in exon 26 of the MDR1 gene, did not have any apparent effect on MDR1 mRNA expression [50]. The reasons for the discrepancy are unknown. One could speculate that racial differences in the relation between C3435T and G2677T should be considered as a possible explanation for seemingly contradictory findings. Also tissue-specific expression of MDR1 mRNA cannot be completely ruled out as an additional mechanism for the differing results [29].

4. 4 Molecular mechanism of MDR1C3435T

Although the MDR1C3435T genotype has been associated with altered P-gp activity and has been extensively studied in different populations, the ac-curate molecular mechanism of the observed associa-tion is still poorly understood. Nevertheless, several mechanisms have been presumed. Firstly, the most popular one is that there exists a linkage between the C3435T SNP and other mutations elsewhere within the MDR1 gene, such as in the promoter/enhancer or intronic regions like T-129C, or in another exon like G2677T/A[51,58]. Secondly, this silent mutation in MDR1C3435T may also reduce translation efficiency to influence functional consequences [29]. Thirdly, it was presumed that the silent mutation might alter or regu-late the processing and translation controlling of mRNA [63,64]. Finally, it is possible that the C3435T transition can impact posttranscriptional modifica-tions or is linked to an important sequence for mRNA processing [59]. Whatever the scenario, the mechanism underlying this association remains to be further studied.

5 MDR1 Polymorphisms and Susceptibil-

ity to Human Diseases

As far as the relationships among the MDR1C3435T genotypes, P-gp expression and function, and suscep-tibility to human diseases are concerned, it is plausible to hypothesize that genotype-dependent P-gp expres-sion may contribute to a certain disease, despite the fact that the physiological role of P-gp has yet to be fully understood.

A low intestinal P-gp expression has been asso-ciated with development of ulcerative colitis (UC). Schaeffeler and colleagues reported that the Africans in Africa exhibited much higher frequency of the CC genotype than the whites in Europe and Asians in Asia and this may constitute a selective advantage against gastrointestinal tract infections [65]. Schwab and co-workers reported that impairment of barrier function in 3435TT subjects could render this geno-type more susceptible to the development of UC. Furthermore, their data showed a two-fold increased risk for development of UC in patients with the MDR13435TT genotype, which supports the notion that lower P-gp expression in this genotype plays a role in the defense against intestinal bacteria and constitutes a risk factor for the development of UC [56]. Potocnik et al. [66] suggested that MDR1 was a potential target for therapy in patients with refractory Crohn’s disease (CD) patients and with UC.

Status of MDR1 genotype has implications for disease risk and therapeutic outcome of AIDS, since all currently marketed HIV protease inhibitors are P-gp substrates[67]. Moreover, P-gp is also expressed in CD56+, CD8+, CD4+, CD19+ and other subpopula-tions in PBMC[16]. Antiretroviral treatment efficacy and intracellular concentrations of HIV protease in-hibitors in CD4+ cells, a major target of the HIV virus, are affected by variable P-gp expression. Indeed, in several studies it was shown that the MDR1 genotype was significantly related to response to antiretroviral treatment. Fellay and coworkers provided evidence

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that after six months of antiretroviral therapy, patients with the 3435TT genotype had a significantly greater increase in CD4+-cell counts and a tend towards a less pronounced viral infection than those patients with the CT or CC genotypes [68].

The MDR1 SNPs may also have consequences in endothelial cells of brain capillaries at blood-brain bar-rier (BBB) sites and a risk factor in Parkinson’s disease. Epidemiological studies suggest that both genetic and environmental factors play a role in the development of Parkinson’s disease (PD)[69]. A significant associa-tion was found between PD patients that were exposed to pesticides and C3435T polymorphism[70]. Furuno et al.[71] reported that the early onset PD subjects were the most in the population of the 3435TT genotype. Therefore, the MDR1 SNPs, which altered P-gp ex-pression in the BBB, might influence the intracellular concentrations of potentially neurotoxic substances leading to an increased susceptibility for PD and/or earlier onset of PD.

In addition, Roberts et al.[48] observed a sig-nificant association between nortriptyline-induced postural hypotension and MDR1C3435T polymor-phisms. Recent evidence has also suggested that the homozygous T-variant was more common in pa-tients with childhood acute lymphoblastic leukemia (ALL)[72,73]. The evidence suggested P-gp could in-fluence the susceptibility to renal epithelial tumors by virtue of MDR1 polymorphisms[44]. These reports suggested that the MDR1C3435T polymorphism might influence treatment with P-gp-dependent drugs. Al-though many factors, such as diet, race, environment and disease state, may influence interindividual variability in the pharmacokinetics of P-gp substrate drugs and therapeutic outcome of certain diseases treated with such drugs, the genetic polymorphisms in the MDR1 gene are one of the primary determi-nants[29]. However, there were other studies that claimed no direct association with C3435T poly-morphism and some diseases, such as UC[74-77]. Therefore, future studies should be carried out to ascertain the relation between MDR1 genetic poly-morphisms and human diseases. 6 Recent Reviews on This Topic

Up to now, there have been at least twenty re-views about MDR1 polymorphisms since 2001. Most of them introduced the MDR1 polymorphisms, ethnic distribution and relevant clinical implications [10,22,24,29,30-36,78-84]. Brinkmann et al.[78] was the first to state pharmacological implications about partial MDR1 SNPs. Subsequently, Fromm outlined the in-fluence of MDR1 polymorphisms on P-gp tissue ex-pression, drug disposition, treatment outcome and disease risk according to the available data［79］. In 2003, Schwab emphasized clinical outcome and dis-ease susceptibility based on their laboratory work [29]. More recent results were reviewed in 2004. Kelleher et al.[80] detailed the association between MDR1 polymorphisms and therapy outcome of inflammatory bowel disease. Marzolini et al. [81] discussed the MDR1 haplotype, environmental factors, and poten-tial confounding factors in the observed effects of MDR1 polymorphisms in vivo. Ishikawa et al. [82] believed that the effects of SNPs on P-gp activity might depend on substrates tested, and functional analysis of SNPs should be used on a wide variety of substrates. He developed a high-speed screening sys-tem and a new structure-activity relationship (SAR) analysis method to quantify the impact of SNPs on the function of MDR1. With the knowledge of altered activity of P-gp in vivo, this review addressed the latest available MDR1 SNP data in relation to differ-ent ethnicity frequencies, pharmacogenetics and clinical relevance. In addition, some controversial conclusions are also summarized.

7 Summary

In order to realize personalized medicine, it is critically important to understand the molecular mechanisms underlying inter-individual differences in drug response, including the pharmacological ef-fect and side effects. Evidence is now accumulating which strongly suggests that drug transporters are one of the determinants governing the pharmacokinetics profile of drugs. Undoubtedly, increasing publications

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confirm that genetic polymorphisms of drug trans-porters are receiving significant attention as a poten-tial determinant of variability in drug disposition and efficacy.

However, at present time, information on this topic is still limited within the actual effect of these genetic polymorphisms on the function of MDR1. Thus, more experimental researches along with ap-propriate clinical studies are necessary to further clar-ify the molecular mechanisms underlying the associa-tion of MDR1 polymorphisms with altered pharma-cokinetics of P-gp. Moreover, it appears that informa-tion, obtained from various analyses about MDR1 haplotype with P-gp expression and function, will help increase our understanding of the phenomenon of variable P-gp activity. Furthermore, newly devel-oped technologies for highly automated genotyping may facilitate such related investigations.This research is still in its infancy; however, we are only now begin-ning to understand the significance of the pharmaco-genomics of P-gp. As can be seen from this review, it would be greatly helpful to achieve some clinical utili-ties, such as individualized drug dosing, improved therapy and prognosis for those diseases whose treat-ments mainly depend on the P-gp substrates if the roles of MDR1 SNPs are rationally defined.

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MDR1基因多态性及其临床相关性研究进展

李艳红1，王永华1，李燕2，杨凌1

1. 中国科学院大连化学物理研究所药用资源开发研究组，大连116023；

2. 大连理工大学, 大连 116012

摘 要：体内外研究证明，人体中P-gp在药物的吸收、分布、代谢和排泄（ADME）过程中发挥了非常重要的作用。多药耐药基因MDR1(ABCB1)是P-gp的编码基因。药物基因组学和遗传药理学研究发现在不同个体中MDR1基因多态性与P-gp 表达和功能的改变密切相关，而且这些多态位点存在基因型分布和等位基因频率的种族差异性。近几年，已陆续发现在MDR1基因中有50处单核苷酸多态性（SNPs）和3处插入与缺失多态性。随后，大量文献报道某些位点的SNPs如C3435T 会使个体患病的易感性增加。因此人们相信，深入研究MDR1基因多态性与P-gp的生理和生化方面的相关性将对个体医疗有着非常深远的意义。文章总结了国外最新的研究进展并结合本实验室的工作着重讨论了4个方面：1) P-gp对药代动力学性质的影响；2) MDR1基因多态性及其对遗传药理学性质的影响；3) MDR1C3435T的单核苷酸多态性与P-gp表达和功能之间的相关性；4) MDR1基因多态性与人类某些疾病之间的相关性。

关键词：P糖蛋白；MDR1；遗传多态性；遗传药理学

作者简介：李艳红（1978-），女，在读博士生，专业方向：生物化工。E-mail: lyhong@https://www.sodocs.net/doc/1c19107308.html,

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MDR1基因多态性及其临床相关性研究进展

作者：李艳红， 王永华， 李燕， 杨凌， LI Yan-Hong， WANG Yong-Hua， LI Yan， YANG Ling

作者单位：李艳红,王永华,杨凌,LI Yan-Hong,WANG Yong-Hua,YANG Ling(中国科学院大连化学物理研究所药用资源开发研究组,大连,116023)， 李燕,LI Yan(大连理工大学,大连,116012)

刊名：

遗传学报

英文刊名：ACTA GENETICA SINICA

年，卷(期)：2006,33(2)

被引用次数：6次

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引证文献(7条)

1.丁征.邓婕.宋洪涛MDR1基因多态性对相关药物药动学影响研究进展[期刊论文]-中国临床药理学与治疗学 2011(10)

2.隋华.周利红.刘宣.殷佩浩.周宁.王炎.孙珏.范忠泽.李琦COX-2介导MDR1/P-gp调控人结肠癌细胞多药耐药的研究[期刊论文]-中国癌症杂志 2011(4)

3.马丽芳.周琦.徐建业.李少林DNA水平电泳检测重庆地区汉族人MDR1C3435T基因多态性[期刊论文]-中国生物制品学杂志 2009(9)

4.吕慧.杜智卓.王薇.赵文理.王易.胡绍燕.柴忆欢江苏地区汉族儿童多药耐药基因3个单核苷酸多态性位点的单倍型研究[期刊论文]-临床合理用药杂志 2011(23)

5.王增.翁琳.程斌ABCB1基因多态性对多西他赛药动学和药效学影响的研究进展[期刊论文]-中国临床药学杂志 2011(1)

6.王琳.陈涵药物体外吸收、分布、代谢和排泄筛选模型[期刊论文]-中国组织工程研究与临床康复 2008(50)

7.李燕基于配体的P糖蛋白底物和抑制剂计算机辅助研究[学位论文]博士 2006

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