MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents

Woodahl, Erica L.; Crouthamel, Matthew H.; Bui, Tot; Shen, Danny D.; Ho, Rodney J. Y.

doi:10.1007/s00280-008-0906-4

Cited by 30 publications

(22 citation statements)

References 18 publications

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“…For example, in vitro experiments have shown that G1199A (Ser400Asn) [50] affects VCR efflux, and that G554T confers amino acid Gly185Val substitution and changed drug specificity of vinblastine and colchicine [51,52]. Both SNPs have very low minor allele frequencies (as reported in the NCBI SNP database) and are therefore not assessed here.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms of the Vincristine Pathway and Response to Treatment in Children with Childhood Acute Lymphoblastic Leukemia

et al. 2014

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Background Vincristine (VCR) is a standard component in the treatment of childhood acute lymphoblastic leukemia (ALL). VCR cytotoxicity is primarily due to its ability to disrupt the formation of microtubules of the mitotic spindle. Patients & methods A total of 17 polymorphisms in regulatory and coding regions of genes controlling VCR targets (TUBB1, MAP4, ACTG1 and CAPG) or potentially influencing VCR levels (ABCB1 and CYP3A5) were investigated for an association with peripheral neuropathy and outcome in childhood ALL patients. Results High-grade neurotoxicity was more frequent in carriers of the A allele of synonymous (Ala310) G to A (rs1135989) variation in the ACTG1 gene. Substitution (rs4728709) in the promoter of the ABCB1 gene had a protective effect against lower grade neurotoxicity and C to A variation (rs3770102) located 17 nucleotides upstream from the transcription start site had a protective effect against high-grade neurotoxicity. Patients with the ABCB1 3435TT genotype had lower event-free survival; the association with event-free survival was not supported by the analysis in the replication patient set. Conclusion The polymorphisms in the ACTG1, CAPG and ABCB1 genes may modulate VCR-related neurotoxicity, whereas the risk of relapse seems not to be affected by the genes of the VCR pathway.

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Section: Discussionmentioning

confidence: 99%

Polymorphisms of the Vincristine Pathway and Response to Treatment in Children with Childhood Acute Lymphoblastic Leukemia

et al. 2014

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“…The synonymous C3435CT and C1236T polymorphisms, together with the missense G2677T/A mutation, encode a haplotype protein with an altered structure that is less responsive to some P‐gp modulators, including cyclosporine, 42 whereas the missense mutation G1199A alters P‐gp's transport activity. 43 , 44 Given the small sample size of our study, we could not conduct any statistical analysis to determine the influence of these polymorphisms on regional P‐gp activity. However, previous imaging studies in healthy volunteers with [ 11 C]‐verapamil have found no effect of polymorphisms in the MDR gene on the uptake of [ 11 C]‐radioactivity 14 , 45 in the brain.…”

Section: Discussionmentioning

confidence: 99%

Regional P-Glycoprotein Activity and Inhibition at the Human Blood–Brain Barrier as Imaged by Positron Emission Tomography

Eyal

Muzi

et al. 2010

Clin Pharmacol Ther

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We evaluated the contribution of P-glycoprotein (P-gp) at the human blood-brain barrier (BBB) to regional brain drug distribution using positron emission tomography (PET). Eleven healthy volunteers underwent PET imaging with [11C]-verapamil before and during cyclosporine A infusion. Regional P-gp inhibition was expressed as cyclosporine A-induced percent change in the brain distributional clearance of verapamil (K1) normalized to the regional blood flow (rCBF). K1 estimates were similar across grey matter regions, lower in the white matter, but all were considerably lower than rCBF. Normalization of K1 by rCBF diminished the grey-to white matter differences. In contrast, the K1 for the pituitary, which resides outside the BBB, approximated rCBF. The magnitude of P-gp inhibition was comparable across BBB-protected brain structures. Our results indicate that P-gp and its inhibition will equally affect the distribution of drugs (and therefore their neuroefficacy and toxicity) in the different brain regions protected by the BBB.

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“…Based on our MDR1 sequence variation analysis, we discovered the novel MDR1 GT1292-3TG nucleotide variation that translates to an amino acid substitution from cysteine to leucine at position 431. We have shown that the recombinant cell system expressing MDR1 wt, MDR1 G1199A , MDR1 G1199T , or MDR1 G571A is a highly reliable and consistent method suitable for evaluating functional changes in P-gp due to sequence variation (8)(9)(10)14).…”

Section: Discussionmentioning

confidence: 99%

A Novel MDR1 GT1292-3TG (Cys431Leu) Genetic Variation and Its Effect on P-glycoprotein Biologic Functions

Crouthamel

Yang

et al. 2010

AAPS J

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P-glycoprotein (P-gp) is a membrane-bound transporter protein that is encoded by the human multidrug resistance gene MDR1 (ABCB1). P-gp recognizes a wide range of xenobiotics, is pivotal in mediating cancer drug resistance, and plays an important role in limiting drug penetration across the blood-brain barrier. MDR1 genetic variation can lead to changes in P-gp function and may have implications on drug pharmacokinetics. We have identified a novel MDR1 (GT1292-3TG) (Cys431Leu) genetic variation through systematic profiling of subjects with leukemia. The cellular and transport function of this variation was investigated with recombinant human embryonic kidney cells expressing MDR1. Compared with the wild type, MDR1 (GT1292-3TG) recombinant cells exhibited a lower drug resistance phenotype for a panel of chemotherapeutic agents. When compared with wild type, MDR1 (GT1292-3TG) recombinant cells exposed exhibited a 75% decrease in IC₅₀ for doxorubicin (162.6 ± 17.4 to 37.9 ± 2.6 nM) and a 50% decrease in IC(50) for paclitaxel (155.7 ± 27.5 to 87.7 ± 9.2 nM), vinblastine (128.0 ± 15.9 to 65.9 ± 5.1 nM), and vincristine (593.7 ± 61.8 to 307.3 ± 17.0 nM). The effects of the Cys431Leu variation, due to MDR1 (GT1292-3TG) nucleotide transition, on P-gp-dependent intracellular substrate accumulation appeared to be substrate dependent where doxorubicin, vinblastine, and paclitaxel exhibit an increased accumulation (p < 0.05), while verapamil and Hoechst33342 exhibit a decreased intracellular concentration compared with wild type (p < 0.05). Collectively, these data suggest MDR1 (GT1292-3TG) variation of P-gp may reduce drug resistance and that subjects with this genotype undergoing chemotherapy with drugs that are transported by P-gp could potentially be more responsive to therapy than those with MDR1 wild-type genotype.

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MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents

Cited by 30 publications

References 18 publications

Polymorphisms of the Vincristine Pathway and Response to Treatment in Children with Childhood Acute Lymphoblastic Leukemia

Polymorphisms of the Vincristine Pathway and Response to Treatment in Children with Childhood Acute Lymphoblastic Leukemia

Regional P-Glycoprotein Activity and Inhibition at the Human Blood–Brain Barrier as Imaged by Positron Emission Tomography

A Novel MDR1 GT1292-3TG (Cys431Leu) Genetic Variation and Its Effect on P-glycoprotein Biologic Functions

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