Multiple drug resistance, antimutagenesis and anticarcinogenesis
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Updated: Aug 16, 2026
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
Lynnette R Ferguson1, Silvio De Flora
1Discipline of Nutrition/ACSRC, School of Medical Sciences, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand. l.ferguson@auckland.ac.nz
Abstract:
Many cells are protected from excess levels of exogenous chemicals, including mutagens and carcinogens as well as pharmaceutical agents, by being actively extruded through the action of one or more of a series of ATP-binding cassette drug transporter proteins. Those known to be important in humans are the multidrug resistance proteins (P-glycoproteins, encoded by the mdr1 and 3 genes), multidrug-resistance-associated proteins (MRP1-7) and the breast cancer resistance protein (BCRP). These proteins have overlapping but distinct cellular locations and substrate specificities, and jointly govern the likelihood of penetration or distribution of a given mutagen or carcinogen into various tissues including the brain, testis, ovaries and fetus. Thus, they can affect the absorption, distribution and excretion of mutagens and carcinogens, as well as of their metabolites and conjugates, in most cases acting to prevent or reduce mutagenesis or carcinogenesis. However, because ABC transporters may limit the success of chemotherapy, there has been a considerable effort by the pharmaceutical industry to develop inhibitors of this transport process, and these are increasing in use. In general, the mutagenicity of many chemicals may be increased at the cellular levels by the action of these inhibitors, while the altered absorption characteristics favour greater uptake into the body. Thus, in many cases, such inhibitors may counter the antimutagenic and anticarcinogenic effect of the multidrug resistance mechanisms. There are exceptions, however. An increasing number of single nucleotide polymorphisms in multidrug resistance genes are being identified in humans, and may account for many of the significant differences in inter-individual susceptibility to exogenous and endogenous mutagenic and carcinogenic insults.
Insights
Cells use ATP-binding cassette (ABC) drug transporters to remove harmful chemicals, protecting against mutagens and carcinogens. Inhibitors of these transporters can increase chemical uptake and mutagenicity, counteracting natural protective mechanisms.
Area of Science:
- Biochemistry
- Pharmacology
- Toxicology
Background:
- Cells possess ATP-binding cassette (ABC) drug transporters, including P-glycoproteins, MRPs, and BCRP, to actively extrude exogenous chemicals like mutagens, carcinogens, and pharmaceuticals.
- These transporters influence the absorption, distribution, and excretion of chemicals, generally acting to prevent or reduce mutagenesis and carcinogenesis.
- Genetic variations (polymorphisms) in ABC transporter genes contribute to individual susceptibility to chemical insults.
Purpose of the Study:
- To elucidate the role of ABC drug transporters in cellular defense against chemical mutagens and carcinogens.
- To examine the impact of ABC transporter inhibitors on chemical uptake, mutagenicity, and the efficacy of natural protective mechanisms.
- To highlight the significance of genetic variations in ABC transporters for inter-individual differences in susceptibility.
Main Methods:
- Review and synthesis of existing literature on ABC drug transporters, their substrates, and their physiological roles.
- Analysis of the effects of pharmaceutical interventions (inhibitors) on ABC transporter function and cellular chemical exposure.
- Examination of the implications of single nucleotide polymorphisms (SNPs) in multidrug resistance genes.
Main Results:
- ABC transporters are crucial for cellular protection against a wide range of exogenous chemicals, including mutagens and carcinogens.
- Inhibitors developed to enhance chemotherapy can paradoxically increase cellular mutagenicity and chemical uptake by blocking these protective transporters.
- Inter-individual differences in susceptibility to chemical insults are partly explained by genetic polymorphisms in ABC transporter genes.
Conclusions:
- ABC drug transporters play a vital role in defending cells and tissues against mutagenic and carcinogenic agents.
- The development and use of ABC transporter inhibitors require careful consideration due to their potential to increase chemical toxicity and counteract protective mechanisms.
- Pharmacogenetic studies focusing on ABC transporter polymorphisms are essential for understanding and predicting individual responses to environmental toxins and therapeutic agents.
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