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Multidrug resistance gene expression in rodents and rodent hepatocytes treated with mitoxantrone
D Schrenk1, A Michalke, T W Gant
1Institute of Toxicology, University of Tübingen, Germany.
Abstract:
Overexpression of P-glycoprotein in tumor cells can represent a severe drawback for cancer chemotherapy. P-glycoprotein acts as an efflux transporter for a variety of chemotherapeutic agents. It is encoded by multidrug resistance (mdr) genes of the subfamily 1 in humans (MDR1) and rodents (mdr1a and 1b). Because mdr1 gene expression is inducible in cultured rat hepatocytes and in rat liver with chemical carcinogens such as 2-acetylaminofluorene or aflatoxin B1, which form DNA-binding electrophiles during their metabolism, we investigated whether the DNA-damaging chemotherapeutic drug mitoxantrone may induce multidrug resistance in rodents and in hepatocytes in primary culture. In H4IIE rat hepatoma cells stably transfected with a luciferase construct containing the rat mdr1b promoter, mitoxantrone caused a concentration-dependent increase in promoter activity. Mdr1 gene expression in cultured rat hepatocytes was enhanced at mitoxantrone concentrations greater than or equal to 0.1 microM and in mouse hepatocytes at 5 microM. In hepatocytes from both species, a correlation was found between mdr1 induction and the inhibition of protein synthesis. In vivo, mitoxantrone was a very powerful inducer of mdr1 gene expression in rat liver and small intestine. In rat kidney, induction of mRNA was lower, and a marginal effect was seen in lung. In contrast with rats, no significant induction of mdr1 gene expression was obtained in mouse liver. Probably as a consequence of inhibition of protein synthesis, mitoxantrone did not lead to a pronounced elevation of P-glycoprotein levels in rat liver and kidney.
Insights
The chemotherapy drug mitoxantrone can induce multidrug resistance by increasing P-glycoprotein (mdr1) gene expression in rodents, particularly in rats, but not significantly in mice. This induction is linked to protein synthesis inhibition.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- P-glycoprotein (P-gp) overexpression in tumors hinders cancer chemotherapy by effluxing drugs.
- P-gp is encoded by multidrug resistance (mdr) genes, with MDR1 in humans and mdr1a/1b in rodents.
- Mdr gene expression is inducible by chemical carcinogens in rodents and hepatocytes.
Purpose of the Study:
- To investigate if the DNA-damaging drug mitoxantrone induces multidrug resistance in rodents and cultured hepatocytes.
- To explore the relationship between mitoxantrone, mdr1 gene expression, and protein synthesis inhibition.
Main Methods:
- Utilized H4IIE rat hepatoma cells with a luciferase reporter construct for rat mdr1b promoter activity.
- Assessed mdr1 gene expression in cultured rat and mouse hepatocytes.
- Evaluated mdr1 gene expression in vivo in rat and mouse tissues (liver, small intestine, kidney, lung).
- Correlated mdr1 induction with protein synthesis inhibition.
Main Results:
- Mitoxantrone increased rat mdr1b promoter activity in a dose-dependent manner.
- Mdr1 gene expression was enhanced in rat hepatocytes (≥0.1 microM) and mouse hepatocytes (5 microM) by mitoxantrone.
- A correlation between mdr1 induction and protein synthesis inhibition was observed in both species' hepatocytes.
- In vivo, mitoxantrone strongly induced mdr1 in rat liver and small intestine, with lower induction in rat kidney and lung.
- No significant mdr1 induction was observed in mouse liver.
Conclusions:
- Mitoxantrone is a potent inducer of mdr1 gene expression in rats, suggesting it can promote multidrug resistance.
- The induction of mdr1 by mitoxantrone in rodents is species-specific, with rats showing a stronger response than mice.
- Protein synthesis inhibition likely plays a role in the mitoxantrone-induced mdr1 expression, although P-glycoprotein levels were not markedly elevated in rat liver and kidney.
