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Mechanisms of resistance to xenobiotics in human therapy
1Institut de Pharmacologie et Biologie Structurale, Toulouse, France.
Abstract:
Xenobiotic resistance is the major cause of failure in human therapies. Because of their serious clinical and economical consequences, resistance phenomena have been intensively studied in the case of antibacterial, anticancer, antipaludic and anti-human immunodeficiency virus-1 therapies. Beside pharmacological factors that can impede the action of the drugs, several cellular mechanisms of resistance have been described. Surprisingly, these mechanisms are conserved among bacteria, eucaryotic cells, parasites and viruses. The efficiency of drugs can be circumvented by alteration of the drug cellular concentration (altered influx, enhanced efflux or sequestration), detoxification, alteration of the drug target, nonactivation or inactivation of the drug, or by enhanced DNA repair.
Insights
Drug resistance, a major cause of therapy failure, involves conserved cellular mechanisms across diverse organisms. Understanding these xenobiotic resistance pathways is crucial for developing effective treatments.
Area of Science:
- Pharmacology and Molecular Biology
- Microbiology and Infectious Diseases
Background:
- Xenobiotic resistance significantly impacts human therapeutic outcomes, leading to substantial clinical and economic burdens.
- Resistance mechanisms are extensively studied in antibacterial, anticancer, antimalarial, and antiviral therapies due to their severe consequences.
Purpose of the Study:
- To review and highlight the conserved cellular mechanisms underlying xenobiotic resistance across various organisms.
- To underscore the importance of understanding these conserved mechanisms for improving therapeutic efficacy.
Main Methods:
- Literature review of studies investigating drug resistance mechanisms.
- Comparative analysis of resistance pathways in bacteria, eukaryotic cells, parasites, and viruses.
Main Results:
- Identified conserved cellular mechanisms of resistance across diverse species.
- Detailed several key resistance strategies: altered drug concentration (influx/efflux), detoxification, target modification, drug inactivation, and enhanced DNA repair.
Conclusions:
- Cellular mechanisms of xenobiotic resistance are remarkably conserved, suggesting a common evolutionary basis.
- Understanding these conserved mechanisms is essential for overcoming drug resistance and improving human therapies.