Alternative titles; symbols
HGNC Approved Gene Symbol: ABCB1
Cytogenetic location: 7q21.12 Genomic coordinates (GRCh38): 7:87,503,017-87,713,295 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q21.12 | {Colchicine resistance} | 120080 | 3 | |
| {Inflammatory bowel disease 13} | 612244 | 3 |
The ABCB1 gene encodes a transmembrane transporter P-glycoprotein that pumps out a wide range of xenobiotic compounds from cells. ABCB1 is expressed in plasma membranes of various cells and organs, including the blood-brain barrier (BBB) endothelium (summary by Seo et al., 2020).
A cDNA encoding p170, a glycoprotein that is increased in membranes from multidrug-resistant cells (including the ones used by Fojo et al. (1986)) was cloned by Riordan et al. (1985).
Roninson et al. (1986) found that multidrug resistance correlated with amplification of 2 related DNA sequences, designated MDR1 and MDR2 (MDR2 has been referred to by others as MDR3; see 171060). These sequences were isolated through their homology with the Chinese hamster mdr gene. MDR1 encodes a 4.5-kb mRNA and was amplified or overexpressed in all multidrug-resistant human cell lines analyzed. No mRNA corresponding to MDR2 was detected. MDR2 DNA sequences are coamplified with MDR1 in some, but not all, multidrug-resistant cell lines.
Ueda et al. (1986) confirmed that the MDR1 gene codes for P-glycoprotein.
Gros et al. (1986) isolated a cDNA that on transfer to an otherwise drug-sensitive cell conferred a complete multidrug-resistant phenotype. Since the cDNA was isolated from a drug-sensitive cell, mutations in the primary sequence of MDR were not required to produce multidrug resistance; thus, amplification is the mechanism of the resistance. Chen et al. (1986) and Gros et al. (1986) found that the class of mammalian membrane glycoproteins implicated in the phenomenon of multidrug resistance in tumor cells bears strong homology to a class of well-studied bacterial transport proteins. Chen et al. (1986) reported the sequence of the MDR cDNA of the human and Gros et al. (1986) reported that of the mouse.
The MDR1 gene encodes a large transmembrane protein that is an integral part of the blood-brain barrier and functions as a drug-transport pump transporting a variety of drugs from the brain back into the blood. The development of simultaneous resistance to multiple structurally unrelated drugs is a major impediment to cancer chemotherapy. Shen et al. (1986) showed that multidrug resistance in human KB carcinoma cells selected in colchicine, vinblastine, or Adriamycin is associated with amplification of specific DNA sequences termed the multidrug resistance locus (MDR1). Increased expression and amplification of MDR1 sequences were also found in multidrug-resistant sublines of human leukemia and ovarian carcinoma cells. Overexpression of P-glycoprotein-1 appears to be a consistent feature of mammalian cells displaying resistance to multiple anticancer drugs and has been postulated to mediate resistance (Kartner et al., 1985; Riordan et al., 1985).
Pastan and Gottesman (1987) gave a useful review.
Fojo et al. (1987) measured MDR1 RNA in human tumors and normal tissues. They found that the MDR1 gene is expressed at a very high level in the adrenal gland; at a high level in the kidney; at intermediate levels in the lung, liver, lower jejunum, colon, and rectum; and at low levels in many other tissues. The MDR1 gene was also expressed in several human tumors, including many but not all tumors derived from the adrenal gland and colon. The authors suggested that measurement of MDR1 RNA might be a valuable tool in the design of chemotherapy.
Trezise et al. (1992) reviewed the parallelism between MDR1 and the cystic fibrosis gene product (CFTR; 602421). Both genes are situated on the long arm of chromosome 7. The proteins are structurally related and both are associated with epithelial chloride channel activities. Trezise et al. (1992) compared their cell-specific expression in the rat by in situ hybridization. In all tissues examined, the 2 genes were found to have complementary patterns of expression, demonstrating exquisite regulation in both cell-specific and temporal manners. They found that expression can switch from one gene to the other, within a single cell, implying that CFTR and MDR1 expression may be coordinately regulated. Expression in the intestine switched from CFTR to MDR1 as the cells migrated across the crypt-villus boundary. Also, a switch from CFTR to MDR1 expression was observed in uterine epithelium upon pregnancy.
Chan et al. (1991) measured levels of P-glycoprotein immunohistochemically in tumor samples in children with neuroblastoma and concluded that expression of P-glycoprotein before treatment predicts the success or failure of therapy.
De Lannoy and Silverman (1992) demonstrated that the MDR1 gene product is the apical membrane protein responsible for the renal secretion of digoxin. This agent has a low therapeutic index and a relatively large and diverse group of coadministered drugs are reported to interact with digoxin, for example, quinidine, verapamil, amiodarone, spironolactone, and cyclosporin, frequently leading to its toxic accumulation. Since digoxin is a prototype for endogenous digitalis-like glycosides, endogenous digitalis-like glycosides may be the natural substrates for P-glycoprotein-1.
Increased levels of P-glycoprotein occur in some osteosarcomas. Baldini et al. (1995) investigated the relationship between P-glycoprotein status and outcome in 92 patients with high-grade osteosarcoma of the extremities who were treated with surgery and chemotherapy. The presence of increased levels of PGY1 in the osteosarcoma were significantly associated with a decreased probability of remaining event-free after diagnosis. In a multivariate analysis, P-glycoprotein status and the extent of tumor necrosis after preoperative chemotherapy were independent predictors of clinical outcome.
The MDR1 P-glycoprotein extrudes a variety of drugs across the plasma membrane. The homologous MDR3 P-glycoprotein is required for phosphatidylcholine secretion into bile. By stable transfection of epithelial cells, van Helvoort et al. (1996) found that MDR1 and MDR3 were localized in the apical membrane. At 15 degrees centigrade, newly synthesized short-chain analogs of various membrane lipids were recovered in the apical albumin-containing medium of MDR1 cells but not control cells. MDR inhibitors and energy depletion reduced apical release. MDR3 cells exclusively released a short-chain phosphatidylcholine. Since no vesicular secretion occurs at 15 degrees centigrade, van Helvoort et al. (1996) concluded that short-chain lipids must have been translocated by the P-glycoproteins across the plasma membrane before extraction into the median by the lipid-acceptor albumin.
HIV-1 protease inhibitors are potent agents in the therapy of HIV-1 infection. However, limited oral absorption and variable tissue distribution complicate their use. Kim et al. (1998) found that P-glycoprotein-1 is involved in the transport of 3 of these protease inhibitors in vitro. After oral administration, plasma concentrations were elevated 2- to 5-fold in mdr1a -/- mice carrying the disrupted MDR1A gene, and with intravenous administration, brain concentrations were elevated 7- to 36-fold. Data demonstrated that P-glycoprotein limits the oral bioavailability and penetration of these agents into the brain. The possibility that higher HIV-1 protease inhibitor concentrations may be obtained by targeted pharmacologic inhibition of P-glycoprotein transport activity was raised by the studies.
MDR1 is expressed in nonmalignant cells, including leukocytes, but physiologic functions for MDR1 had been poorly defined. Randolph et al. (1998) identified a physiologic function for MDR1 during the mobilization of antigen-presenting dendritic cells and helped elucidate how these cells migrate from the periphery to lymph nodes to initiate T lymphocyte-mediated immunity.
Synold et al. (2001) showed that SXR (603065) regulates drug efflux by activating expression of the MDR1 gene. Paclitaxel (Taxol), a commonly used chemotherapeutic agent, activated SXR and enhanced P-glycoprotein-mediated drug clearance. In contrast, docetaxel (Taxotere), a closely related antineoplastic agent, did not activate SXR and displayed superior pharmacokinetic properties. Docetaxel's silent properties reflect its inability to displace transcriptional corepressors from SXR. Synold et al. (2001) also found that ET-743, a potent antineoplastic agent, suppressed MDR1 transcription by acting as an inhibitor of SXR. Their findings demonstrated how the molecular activities of SXR can be manipulated to control drug clearance.
Wang et al. (2006) developed 11 MDR1-positive multidrug-resistant variants of ovarian cancer cell lines by continuous exposure to taxanes. In 9 of the resistant variants, microarray analysis revealed a cluster of genes that were coactivated with MDR1 in chromosome 7. In 6 of these variants, regional activation was driven by gene copy number alterations, with low-level gains or high-level amplifications spanning the involved region. However, the other 3 variants showed increased gene expression without concomitant gene copy number changes.
Sims-Mourtada et al. (2007) showed that inhibition of Sonic hedgehog (SHH; 600725) signaling increased the response of human cancer cell lines to multiple structurally unrelated chemotherapies. SHH activation induced chemoresistance in part by increasing drug efflux in an ABC transporter-dependent manner. SHH signaling regulated expression of ABCB1 and ABCG2 (603756), and targeted knockdown of ABCB1 and ABCG2 expression by small interfering RNA partially reversed SHH-induced chemoresistance.
Bao et al. (2012) identified MDR1 as a target of microRNA-128 (MIR298; 614914). Expression of mature processed MIR298 was downregulated in a doxorubicin-resistant MDA-MB-231 subclone compared with parental doxorubicin-sensitive MDA-MB-231 cells. Downregulated MIR298 correlated with upregulated cytoplasmic expression of MDR1 and MDR1-dependent nuclear exclusion of doxorubicin. Overexpression and knockdown studies and use of an MIR298 mimic and reporter genes revealed that MIR298 downregulated MDR1 expression via a MIR298-binding site in the 3-prime UTR of the MDR1 transcript. Downregulated MDR1 expression permitted nuclear uptake of doxorubicin and doxorubicin-mediated cytotoxicity. MIR298 downregulation in doxorubicin-resistant MDA-MB-231 cells appeared to be due to reduced cellular content of the miRNA-processing enzyme Dicer (606241) and was associated with profound alterations in the cellular miRNA profile.
Katayama et al. (2014) found that PPP2R3C (615902) stimulated protein phosphatase-5 (PP5, or PPP5C; 600658)-dependent dephosphorylation of serine-phosphorylated P-glycoprotein. Knockdown of PP5/PPP2R3C increased P-glycoprotein expression and lowered cell sensitivity to chemotherapeutic agents. Katayama et al. (2014) concluded that PPP2R3C/PP5 negatively regulates P-glycoprotein expression and function.
Wu et al. (2019) found that Mycobacterium tuberculosis infection enhanced MDR1 expression in monocyte-derived macrophages (MDMs) and in lungs of infected mice. This MDR1 upregulation in human macrophages required virulence factors released by M. tuberculosis and the Esx1 secretion system. M. tuberculosis infection enhanced expression of MIR431 (611708), which resulted in MIR431-mediated suppression of HSF1 (140580) and increased MDR1 expression in MDMs. Enhanced MDR1 expression increased extrusion of antituberculosis drugs from the macrophage, lowered the effective intracellular minimum inhibitory concentration, and promoted survival of M. tuberculosis during antibiotic treatment.
Fojo et al. (1986) found that both MDR1 and MDR2 map to chromosome 7. This was done by hybridization of these DNA sequences with DNA from a panel of human-mouse somatic cell hybrids and from individual chromosomes separated by fluorescence-activated chromosome sorting.
Trent and Witkowski (1987) used both in situ hybridization and the study of a fibroblast cell line and a human/mouse somatic cell hybrid with deletions of chromosome 7 to assign the human MDR1 gene to the 7q21-q31 region.
Callen et al. (1987) localized the MDR1 locus to 7q21.1 by in situ hybridization.
Using in situ hybridization, Martinsson and Levan (1987) demonstrated that the corresponding gene in the mouse is on chromosome 5.
In the course of examining different P-glycoproteins for acquired mutations in the course of chemotherapy, Mickley et al. (1997) identified a gene rearrangement involving the MDR1 gene of a cell line as a novel mechanism for acquired resistance. Deletion of the first 68 residues of MDR1 in an adriamycin-selected cell line after a 4;7 translocation, t(4q;7q), resulted in a hybrid mRNA containing sequences from both MDR1 and a novel gene on chromosome 4. Further selection resulted in amplification of a hybrid gene. Expression of the hybrid mRNA was controlled by the chromosome 4 gene, providing a model for overexpression of MDR1. Additional hybrid mRNAs in other drug-selected cell lines and in patients with refractory leukemia, with MDR1 juxtaposed 3-prime to an active gene, established random chromosomal rearrangements with overexpression of hybrid MDR1 mRNAs as a mechanism of acquired drug resistance.
Crystal Structure
Dawson and Locher (2006) determined the crystal structure of the bacterial ABC transporter (Sav1866) from Staphylococcus aureus at 3.0-angstrom resolution. The homodimeric protein consists of 12 transmembrane helices in an arrangement that is consistent with crosslinking studies and electron microscopic imaging of the human multidrug resistance protein MDR1, but critically different from that reported for the bacterial lipid flippase MsbA. The observed, outward-facing conformation reflects the ATP-bound state, with the 2 nucleotide-binding domains in close contact and the 2 transmembrane domains forming a central cavity, presumably the drug translocation pathway, that is shielded from the inner leaflet of the lipid bilayer and from the cytoplasm, but exposed to the outer leaflet and the extracellular space.
Aller et al. (2009) determined the x-ray structure of apo P-glycoprotein at 3.8 angstroms. An internal cavity of about 6,000 angstroms is cubed with a 30-angstrom separation of the 2 nucleotide-binding domains. Two additional P-glycoprotein structures with cyclic peptide inhibitors demonstrated distinct drug-binding sites in the internal cavity capable of stereoselectively that is based on hydrophobic and aromatic interactions. Apo and drug-bound P-glycoprotein structures have portals open to the cytoplasm and the inner leaflet of the lipid bilayer for drug entry. The inward-facing conformation represents an initial stage of the transport cycle that is competent for drug binding.
Electron Paramagnetic Resonance Spectroscopy
Dong et al. (2005) used site-directed spin labeling and electron paramagnetic resonance spectroscopy to characterize the conformational motion that couples energy expenditure to substrate translocation in the multidrug transporter MsbA. In liposomes, ligand-free MsbA samples conformations that depart from the crystal structures, including looser packing and water penetration among the periplasmic side. ATP binding closes the substrate chamber to the cytoplasm while increasing hydration at the periplasmic side, consistent with an alternating access model. Accentuated by ATP hydrolysis, the changes in the chamber dielectric environment and its geometry provide the likely driving force for flipping amphipatic substrates and a potential exit pathway.
Double Electron-Electron Resonance (DEER)
Verhalen et al. (2017) used double electron-electron resonance and molecular dynamics simulations to describe the ATP- and substrate-coupled conformational cycle of the mouse ABC efflux transporter P-glycoprotein, which has a central role in the clearance of xenobiotics and in cancer resistance to chemotherapy. They introduced pairs of spin labels at residues selected to track the putative inward-facing to outward-facing transition. The findings illuminated how ATP energy is harnessed in the NBDs in a 2-stroke cycle and elucidated the consequent conformational motion that reconfigures the transmembrane domain, 2 critical aspects of P-glycoprotein transport mechanism. Verhalen et al. (2017) concluded that, along with a fully atomistic model of the outward-facing conformation in membranes, the insight into P-glycoprotein conformational dynamics integrated mechanistic and structural data into a novel perspective on ATP-coupled transport and revealed mechanistic divergence within the efflux class of ABC transporters.
Dastvan et al. (2019) used DEER to uncover the basis of stimulation of P-glycoprotein (ABCB1) ATP hydrolysis by multiple substrates and illuminate how substrates and inhibitors differentially affect its transport function. The results revealed that substrate-induced acceleration of ATP hydrolysis correlates with stabilization of a high-energy, post-ATP hydrolysis state characterized by structurally asymmetric nucleotide-binding sites. By contrast, this state is destabilized in the substrate-free cycle and by high-affinity inhibitors in favor of structurally symmetric nucleotide-binding sites.
Cryoelectron Microscopy
Alam et al. (2019) determined the 3.5-angstrom cryoelectron microscopy structure of substrate-bound human ABCB1 reconstituted in lipidic nanodiscs, revealing a single molecule of the chemotherapeutic compound paclitaxel (Taxol) bound in a central, occluded pocket. A second structure of inhibited, human-mouse chimeric ABCB1 revealed 2 molecules of zosuquidar occupying the same drug-binding pocket. Minor structural differences between substrate- and inhibitor-bound ABCB1 sites are amplified toward the nucleotide-binding domains, revealing how the plasticity of the drug-binding site controls the dynamics of the ATP-hydrolyzing nucleotide-binding domains. Ordered cholesterol and phospholipid molecules suggested how the membrane modulates the conformational changes associated with drug binding and transport.
Association With Multidrug Resistance
Croop et al. (1988) reviewed the genetics of multidrug resistance.
Slovak et al. (1987) found changes in 7q as the most frequent aberration in cell lines acquiring resistance to doxorubicin. Gene amplification in human tumor cells is frequently mediated by extrachromosomal elements such as double minute chromosomes (DMs). DMs can be formed from smaller submicroscopic circular precursors referred to as episomes. Ruiz et al. (1989) demonstrated autonomously replicating episomes containing MDR1 genes in a multidrug-resistant human cell line.
Hoffmeyer et al. (2000) described the identification and distribution of 15 polymorphisms in the human MDR1 gene in a human population. One of these polymorphisms showed significant correlation with MDR1 expression levels and P-glycoprotein (PGP) activity in vivo. PGP expression and function in the duodenum was determined by Western blot and quantitative immunohistology and by plasma concentrations after orally administered digoxin. A 3435C-T transition in exon 26 of MDR1 correlated with expression level and function (171050.0002). Individuals homozygous for this polymorphism had significantly lower duodenal MDR1 expression and the highest digoxin plasma levels. Homozygosity for this variant was observed in 24% of 188 individuals studied. Thus, this polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of MDR1.
To determine whether the 3435C-T polymorphism actually affects P-glycoprotein activity, Kimchi-Sarfaty et al. (2007) expressed wildtype and polymorphic P-glycoproteins in HeLa cells and several other cell systems. They found that although mRNA protein levels were similar between polymorphic and wildtype P-glycoprotein, there was an altered conformation in the polymorphic protein. Kimchi-Sarfaty et al. (2007) hypothesized that the presence of a rare codon marked by the synonymous polymorphism affects the timing of cotranslational folding and insertion of P-glycoprotein into the membrane, thereby altering the structure of substrate and inhibitor interaction sites.
Association With Inflammatory Bowel Disease
Crohn disease (CD) and ulcerative colitis (UC) are phenotypically overlapping chronic inflammatory bowel diseases for which suggestive evidence for linkage at 7q has been reported (IBD13; 612244). Brant et al. (2003) sequenced exonic regions of candidate gene ABCB1 and tested for IBD association in a large, multicenter North American cohort of IBD patients. Significant association of the ala893 allele of the ala893-to-ser/thr polymorphism (A893S/T; 171050.0003) was found with IBD by both case-control analysis (p = 0.002) and the pedigree disequilibrium test, but not with the asn21-to-asp or 3435C-T (171050.0002) polymorphisms.
Ho et al. (2006) analyzed 6 tagging SNPs representing haplotypic variations of the ABCB1 gene in 249 UC and 179 CD patients and 260 controls and found a highly significant association between the common haplotypes and UC (p = 4.22 x 10(-7)), but not CD. The association was dependent on a single tSNP, a G/A variant in intron 3 of ABCB1 (rs3789243), with the 'G' and 'A' alleles conferring susceptibility and protection, respectively. The association with UC was strongest in patients with extensive disease (p = 1.7 x 10(-7)). Noting that the effect of rs3789243 was independent of the 3435C-T SNP, Ho et al. (2006) suggested that the previously identified variants 3435C-T and 2677G-T/A (A893S/T) are not causal variants but lie in linkage disequilibrium (LD) with the causal variant; they further stated that it was premature to suggest that rs3789243 itself is the causal variant, noting that it is possible that the extent of LD could be so high that the causal variant could lie anywhere in the LD block on the associated chromosome.
Associations Pending Confirmation
For discussion of a possible association between genetic variation in the ABCB1 gene and the dosage of methadone required for proper treatment of heroin addiction, see susceptibility to opioid dependence (610064).
In a 14-year-old Korean girl, born of unrelated parents, with a recurrent reversible episodic encephalopathy associated with acute febrile or afebrile illness, Seo et al. (2020) identified compound heterozygous loss-of-function variants in the ABCB1 gene: a nonsense variant (P1182X) and a splice site variant (c.2786+1G-T). (In the article, the nonsense variant is listed as P1182X in the text and figure 1 but as Q1182X in the supplemental material.) The variants were found by trio-based whole-exome sequencing and confirmed by Sanger sequencing. The parents were each heterozygous for one of the mutations. Neither was present in the gnomAD database or in 1,020 Korean exomes. RT-PCR analysis of patient-derived cells showed that the splice site variant resulted in the production of several abnormal transcripts leading to a frameshift or premature protein termination. The nonsense variant was also associated with decreased transcript, but some wildtype protein was predicted to be produced. The proband had a similarly affected twin sister, but DNA from that sister was not sequenced. Both girls had normal growth and normal development without cognitive impairment. Before 5 years of age, both had experienced several acute febrile or afebrile illnesses without complications. However, around 5 or 5.5 years of age, both developed recurrent acute encephalopathic episodes that began during acute illnesses, including fever, vomiting, and abdominal pain. The episodes were characterized by irritability and agitation that progressed to decreased consciousness and obtundation with generalized spasticity and hyperreflexia. Visual hallucinations occurred at times. The episodes lasted from hours to a day and occurred multiple times during the illness. The patients recovered completely without any sequelae when treated with supportive care, such as hydration, antibiotics, antiemetics, and antihistamines. Serum and CSF analyses during the episodes were normal, as were brain imaging and EEG. PET imaging of the brain in the affected twin girls showed increased uptake and prolonged retention of carbon-labeled verapamil, an ABCB1-targeting agent, compared to their parents and an unaffected sister. These findings suggested that the episodes may be triggered by a specific molecule. Based on the association of the episodes with fever and illness, Seo et al. (2020) hypothesized that exogenous lipopolysaccharide (LPS) may be a trigger. Treatment of Abcb1-null mice with LPS resulted in persistent upregulation and decreased clearance of certain cytokines in the brain compared to wildtype mice who were able to clear the cytokines faster. No additional patients with this phenotype and genotype were identified through local communication or the GeneMatcher program. Seo et al. (2020) concluded that the phenotype in these sisters resulted from reduced xenobiotic clearance in the brain due to lack of ABCB1, and suggested that the molecular trigger of the clinical response may be associated with impaired cytokine clearance in the brain. The proband also carried compound heterozygous missense variants (V902M and G222R) in the ODZ4 gene (TENM4; 610084) that were inherited from the unaffected parents.
Tang et al. (2004) reported a detailed characterization of the haplotype and linkage disequilibrium architecture of the entire 200 kb of the MDR1 gene in 5 world populations, namely, Chinese, Malays, Indians, Caucasians, and African-Americans. The authors observed varied haplotype diversity across the entire gene in the different populations. The major haplotype mh5, which contains the subhaplotype e12/1236T-e21/2677T-e26/3435T, was highly represented among the 4 non-African populations, while mh7, which contains the subhaplotype e12/1236C-e21/2677G-e26/3435C, accounted for over a third of African-American chromosomes. These observations were considered inconsistent with a simple population evolution model, but instead suggestive of recent historical events that have maintained such long-range linkage disequilibrium. Using a modified long-range haplotype test, the authors found statistically significant evidence of recent positive selection for the e21/2677T and e26/3435T alleles in the Chinese population, and for the e26/3435T allele in the Malay population. The authors suggested that independent mutational events may have occurred on the mh5 and mh7 haplotypes of the MDR1 gene to confer positive selection in the non-African and African-American populations, respectively.
Schinkel et al. (1994) generated mice homozygous for a disruption of the mdr1a gene. The mice were viable and fertile and appeared phenotypically normal, but they displayed an increased sensitivity to the centrally neurotoxic pesticide ivermectin (100-fold) and to the carcinostatic drug vinblastine (3-fold). By comparison of the homozygous null mice with wildtype mice, they found that the mdr1a P-glycoprotein is the major P-glycoprotein in the blood-brain barrier and that its absence results in elevated drug levels in many tissues, especially in brain, and in decreased drug elimination.
Ivermectin is produced by the ground-dwelling bacterium Streptomyces avermitilis. It is the drug of choice to treat river blindness (onchocerciasis), a blinding and debilitating disease caused by a parasitic nematode worm, which affects 18 million people in West Africa and middle America (Taylor et al., 1990). Pulliam et al. (1985) reported extreme ivermectin sensitivity in some inbred dogs of the collie breed. The hypersensitivity was associated with increased ivermectin accumulation in the brain. Schinkel et al. (1994) suggested that these dogs had a genetic deficiency in an MDR1-type P-glycoprotein. Hypersensitivity to ivermectin has not been recognized in humans.
Panwala et al. (1998) found that Mdr1a -/- mice developed a severe, spontaneous intestinal inflammation when maintained under specific pathogen-free conditions. The pathology of the intestinal inflammation was similar to that of human IBD and was defined by dysregulated epithelial growth and leukocytic infiltration into the lamina propria of the large intestine. Treatment with oral antibiotics prevented development of disease and resolved active inflammation. Lymphoid cells from Mdr1a -/- mice with active colitis were reactive to intestinal bacterial antigens, indicating that enhanced immune responses to normal bacterial flora occurs during IBD in animals with an intact immune system. Panwala et al. (1998) concluded that development of colitis results from a defect in the intestinal epithelial barrier.
Using naturally occurring Mdr1a mutant mice of the CF-1 outbred mouse stock that lacked the Mdr1a P-glycoprotein (Umbenhauer et al., 1997), and therefore phenotypically resembled mice with a targeted disruption of Mdr1a (Schinkel et al., 1994), Lankas et al. (1998) showed that absence of the Mdr1a P-gp is associated with enhanced sensitivity of the fetus to an isomer of the pesticide ivermectin. They further showed that enhanced fetal drug penetration paralleled the increased ivermectin sensitivity in the mutant fetuses. Smit et al. (1999) found that in the null mice of the form created by Schinkel et al. (1994), intravenous administration of P-gp substrate drugs to pregnant dams revealed that much more drug entered the null fetuses than entered the wildtype fetuses. Furthermore, placental P-gp activity could be completely inhibited by oral administration of P-gp blockers to heterozygous mothers. The findings implied that the placental drug transport P-glycoprotein is of great importance in limiting the fetal penetration of various potentially harmful or therapeutic compounds and demonstrated that this P-gp function can be abolished by pharmacologic means. The latter principle could be applied clinically to improve pharmacotherapy of the unborn child.
Some specific subgroups of mice and dogs are exquisitely sensitive to the neurologic actions of ivermectin. Studying a subpopulation of collie dogs, Mealey et al. (2001) found that a deletion mutation of the MDR1 gene is associated with ivermectin sensitivity. The 4-bp deletion resulted in a frameshift, generating several stop codons that prematurely terminate the P-glycoprotein gene product. The homozygous normal or heterozygous animals did not display increased sensitivity.
The deletion mutation in the canine MDR1 gene that is associated with drug sensitivities was found in 2 breeds from the collie lineage. Neff et al. (2004) exploited breed phylogeny and reports of drug sensitivity to survey other purebred populations that might be genetically at risk. They found that the same allele, which they designated MDR1-1-del, segregated in 7 additional breeds, including 2 sighthounds that were not expected to share collie ancestry. A mutant haplotype that was conserved among affected breeds indicated that the allele was identical by descent. Based on breed histories and the extent of lineage disequilibrium, Neff et al. (2004) concluded that all dogs carrying the deletion mutation are descendants of a dog that lived in Great Britain before the genetic isolation of breeds by registry (ca 1873).
The preferential resistance to colchicine (120080) in a colchicine-selected multidrug-resistant cell line was shown to be caused by a spontaneous mutation in the MDR1 gene that resulted in a gly185-to-val change in P-glycoprotein (Choi et al., 1988). Safa et al. (1990) presented evidence suggesting that this amino acid substitution affects not the initial drug-binding site but another site associated with the release of P-glycoprotein-bound drugs to the outside of the cell.
Hoffmeyer et al. (2000) found a significant correlation between a polymorphism, 3435C-T, (rs1045642) in exon 26 of MDR1 with expression levels and function of MDR1. Homozygosity for this variant was observed in 24% of 188 Caucasians studied.
People who are homozygous for the 3435T allele of MDR1 have on average substantially lower intestinal P-glycoprotein expression than those homozygous for the C allele. Schaeffeler et al. (2001) found that 142 of 172 (83%) West Africans (Ghanaians) and 25 of 41 (61%) African Americans were homozygous for the C allele, whereas only 139 of 537 (26%) Caucasians and 7 of 50 (34%) Japanese showed this genotype (P less than 0.0001). The frequency of the C allele was 90% in Ghanaians, compared with 50% in Caucasians. The authors suggested that the increased C allele results from a selective advantage against tropical gastrointestinal tract infections, particularly viral infections. Schaeffeler et al. (2001) noted that the findings may indicate clinically important consequences for treatment of African populations with P-glycoprotein substrates such as HIV-1 protease inhibitors and cyclosporin A, including lower bioavailability and lower plasma levels of the drugs due to greater MDR1-induced drug efflux.
Drug-resistant epilepsy occurs in up to one-third of patients. Compared to 115 patients with drug-responsive epilepsy, Siddiqui et al. (2003) found that 200 patients with drug-resistant epilepsy had increased frequency of the position 3435 C/C genotype compared to the T/T genotype (odds ratio of 2.66). However, the authors noted that the polymorphism fell within an extensive block of linkage disequilibrium spanning much or all of the gene, suggesting that the polymorphism may be linked with the causal variant. Tan et al. (2004) failed to find an association between the C/C genotype and drug-resistant epilepsy in a replication study of 401 drug-resistant and 208 drug-responsive patients with epilepsy.
Zimprich et al. (2004) genotyped an ABCB1 haplotype defined by 3 single-nucleotide polymorphisms in exons 12 (1236C-T), 21 (2677G-T), and 26 (3435C-T) in 210 patients with mesial temporal lobe epilepsy (e.g., 608096), who were stratified according to their degree of drug resistance, and 228 controls. There were more homozygous carriers of the CGC haplotype in patients with higher pharmacoresistance (odds ratio of 4.67), suggesting that the degree of pharmacoresistance may be modulated by the ABCB1 gene.
Among 281 and 425 epileptic patients treated with phenytoin and carbamazepine, respectively, Tate et al. (2005) found no association between the ABCB1 3435C-T polymorphism and maximum drug dosage needed to control symptoms.
Kimchi-Sarfaty et al. (2007) determined that although mRNA protein levels were similar between 3435C-T polymorphic and wildtype P-glycoprotein, there was an altered conformation in the polymorphic protein. Kimchi-Sarfaty et al. (2007) hypothesized that the presence of a rare codon marked by the synonymous polymorphism affects the timing of cotranslational folding and insertion of P-glycoprotein into the membrane, thereby altering the structure of substrate and inhibitor interaction sites.
In a large, multicenter North American cohort of patients with inflammatory bowel disease (IBD13; 612244), Brant et al. (2003) sequenced exonic regions of the ABCB1 gene and found that the common allele, ala893, of the triallelic ala893-to-ser/thr (A893S/T) variant is associated with Crohn disease, with undertransmission of the 893ser (common) and 893thr (rare) variants. Similar, nonsignificant trends were observed in a smaller subset with ulcerative colitis. The ala893 variant has decreased activity compared with the 893ser variant.
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