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Multidrug resistance gene family and chemical carcinogens
S S Thorgeirsson1, J A Silverman, T W Gant
1Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Abstract:
The data discussed in this review indicate that the coordinated induction of both the mdr gene family and a subfamily of the cytochrome P-450 supergene family provide a unified response of the organism to prevent lethal accumulation of xenobiotics. Consequently, a distinct physiological role for the mdr multigene family now exists. Furthermore, recent evidence suggests the existence of multiple receptors with overlapping substrate specificity that are involved in the induction of both mdr and P-4501A gene families. The increased expression of mdr gene(s) in the early stages of liver carcinogenesis and presumably in other tissues is associated with the development of xenobiotic resistance that is observed in the preneoplastic cell populations. These observations may have important clinical implications and may provide an explanation for resistance to chemotherapy of tumors in organs such as liver and colon that are frequently exposed to both environmental and dietary xenobiotics.
Insights
The multidrug resistance (MDR) gene family and cytochrome P-450 work together to protect the body from toxic substances. This coordinated response is crucial for preventing xenobiotic accumulation and may explain chemotherapy resistance in certain cancers.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- The multidrug resistance (MDR) gene family and cytochrome P-450 (CYP) enzymes are critical for xenobiotic metabolism and cellular defense.
- Previous research suggested independent roles for these gene families in response to foreign compounds.
Purpose of the Study:
- To review evidence for a coordinated induction of MDR and CYP gene families as a unified protective mechanism.
- To explore the physiological significance of the MDR multigene family.
- To investigate the role of shared receptors in the induction of MDR and CYP1A genes.
Main Methods:
- Review of existing scientific literature and data.
- Analysis of gene expression patterns in response to xenobiotics.
- Examination of receptor-substrate interactions.
Main Results:
- Coordinated induction of MDR and CYP gene families provides a unified response to prevent lethal xenobiotic accumulation.
- Evidence supports a distinct physiological role for the MDR multigene family.
- Multiple receptors with overlapping specificity are involved in inducing both MDR and CYP1A genes.
- Increased MDR gene expression in early carcinogenesis correlates with xenobiotic resistance in preneoplastic cells.
Conclusions:
- The MDR gene family plays a significant physiological role in xenobiotic defense.
- Understanding the coordinated induction of MDR and CYP genes offers insights into xenobiotic resistance.
- These findings have potential clinical implications for chemotherapy resistance in organs like the liver and colon.