Neither P-gp SNP variants, P-gp expression nor functional P-gp activity predicts MDR in a preliminary study of plasma

Stephen Drain1, Mark A Catherwood, Anthony J Bjourson

  • 1Haemato-Oncology Laboratory, Belfast HSC Trust, Belfast City Hospital, Northern Ireland BT9 7AB.

Abstract

Insights

Researchers developed a new flow cytometry method to measure P-glycoprotein (P-gp) activity in plasma cell myeloma (PCM) patients. This study explored the impact of ABCB1 gene variants on P-gp function in PCM, finding no significant associations.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Multidrug resistance (MDR) via P-glycoprotein (P-gp) hinders plasma cell myeloma (PCM) treatment.
  • Accurate methods to assess P-gp activity in patient samples are currently lacking.

Purpose of the Study:

  • To establish and optimize flow cytometry methods for determining P-gp activity in PCM patient samples.
  • To investigate the functional impact of ABCB1 single nucleotide polymorphisms (SNPs) in patients with PCM.

Main Methods:

  • Utilized advanced flow cytometry techniques to measure P-gp activity in PCM tumor cells.
  • Employed PCR-based approaches for a pilot study on ABCB1 SNPs in PCM patients.

Main Results:

  • No significant associations were found between P-gp activity/expression and PCM subgroups.
  • No association between P-gp expression and ABCB1 SNPs; a trend towards reduced activity for rs1045642 (P=0.121) was observed.

Conclusions:

  • A novel, clinically applicable flow cytometry method for P-gp and MRP activity assessment in PCM was developed and optimized.
  • This study represents the first comprehensive analysis of ABCB1 SNPs' impact from genome to proteome in PCM.
  • The described methods can be adapted for studying drug-resistant populations and other hematological malignancies.

Related Concept Videos

Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters01:16

Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters

The pharmacogenetics of drug transporters is increasingly recognized as a critical factor influencing interindividual variability in drug absorption, distribution, and elimination. These membrane-bound proteins regulate drugs' movement across cellular barriers by actively pumping them out (efflux) or facilitating their uptake (influx). Among the major transporter families, ATP-binding cassette (ABC) and solute carrier (SLC) transporters play particularly prominent roles. Genetic polymorphisms...
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu01:29

Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu

Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
Pharmacogenomics: Identification of New Drug Targets01:29

Pharmacogenomics: Identification of New Drug Targets

Advances in genomics have profoundly influenced drug discovery by increasing both the speed and accuracy of pharmaceutical development. Pharmacogenomics, which examines how genetic variation influences drug response, facilitates the identification of novel therapeutic targets and enables patient stratification for personalized treatment. These strategies contribute to improved drug efficacy, minimized adverse effects, and more efficient clinical trial design.Mapping genetic differences...
Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes01:28

Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes

Cytochrome P450 (CYP450) enzymes are a superfamily of heme-containing monooxygenases that play a pivotal role in Phase I drug metabolism by catalyzing oxidation and reduction reactions.These enzymes transform lipophilic xenobiotics into more hydrophilic metabolites, facilitating subsequent Phase II conjugation and eventual excretion. The CYP450 family is classified into families (e.g., CYP1–CYP3) and subfamilies (e.g., CYP2A, CYP2C), based on amino acid sequence homology.CYP450 isoenzymes,...
Principles of Pharmacogenetics: Types of Genetic Variants01:27

Principles of Pharmacogenetics: Types of Genetic Variants

The human genome is over 99.9% identical between individuals, yet genetic differences exist at millions of bases. The human genome contains approximately 3 million variant positions per individual, many of which are heterozygous, contributing to genetic diversity and individual traits. Genetic variations include single-nucleotide polymorphisms (SNPs), insertions, deletions, and copy number variations (CNVs).SNPs, the most common variation, involve single-base changes in DNA. These can be...