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Delivery of mevalonate to murine extrahepatic tissues via mini-osmotic pumps
Robin E Duncan1, Ahmed El-Sohemy, Michael C Archer
1Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Introduction:
Mevalonate and derivatives of mevalonate metabolism play important roles in cellular metabolism and may be especially important in rapidly growing cancer cells. A method for delivering mevalonate to extrahepatic tissues, where many tumors of interest in experimental cancer research are found, has not been reported.
Methods:
Mice were administered mevalonate subcutaneously via implanted Alzet mini-osmotic pumps. Microsomes isolated from samples of liver, mammary gland, and colon were assayed for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity. This enzyme is responsible for endogenous mevalonate synthesis, and its down-regulation is evidence that mevalonate has reached the tissue. Serum cholesterol levels were determined to exclude the possibility that down-regulation of HMG-CoA reductase was caused by an influx of circulating cholesterol.
Results:
HMG-CoA reductase activity was decreased in livers, mammary glands, and colons of mice given mevalonate via mini-osmotic pumps. Serum cholesterol levels did not rise in these mice, precluding an indirect effect of serum lipoproteins on HMG-CoA reductase regulation.
Discussion:
Mevalonate can be effectively delivered to cells of the mammary gland and colon of mice via subcutaneously implanted mini-osmotic pumps.
Insights
Subcutaneous mini-osmotic pumps effectively deliver mevalonate to extrahepatic tissues, including mammary glands and colon, in mice. This method enables targeted delivery for cancer research without altering serum cholesterol levels.
Area of Science:
- Biochemistry
- Cancer Research
- Pharmacology
Background:
- Mevalonate metabolism is crucial for cellular functions, particularly in rapidly proliferating cancer cells.
- Effective delivery of mevalonate to extrahepatic tissues, common sites for experimental tumors, remains a challenge.
Purpose of the Study:
- To establish and validate a method for delivering mevalonate to extrahepatic tissues in mice.
- To assess the impact of delivered mevalonate on endogenous synthesis pathways.
Main Methods:
- Mevalonate was administered subcutaneously to mice using implanted Alzet mini-osmotic pumps.
- 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity was measured in liver, mammary gland, and colon microsomes.
- Serum cholesterol levels were monitored to rule out indirect regulatory effects.
Main Results:
- A significant decrease in HMG-CoA reductase activity was observed in the liver, mammary gland, and colon.
- Serum cholesterol levels remained stable, indicating that the observed enzyme down-regulation was a direct effect of mevalonate delivery.
- This confirms successful delivery of mevalonate to target extrahepatic tissues.
Conclusions:
- Subcutaneous implantation of mini-osmotic pumps provides an effective means of delivering mevalonate to extrahepatic tissues in mice.
- This delivery method holds promise for experimental cancer research involving tumors in tissues like the mammary gland and colon.
