Valproic acid, used widely in treating epilepsy, has been found to reduce fat accumulation in the liver and lower blood sugar levels in the blood of obese mice, a new study reveals.
Studying the ways in which the cytochrome P450 family of enzymes processes valproic acid, the Johns Hopkins biochemists found that it can activate the protein AMPK, which was already known to be a good drug target for treating metabolic disorders like type 2 diabetes and obesity.
The Bumpus laboratory studies how drugs are processed in cells by enzymes of the cytochrome P450 family. Humans have 57 of these enzymes, and several of them work on the drug valproic acid. In the course of their research, Namandje Bumpus, Ph.D., assistant professor of pharmacology, and postdoctoral fellow Lindsay Avery, Ph.D., found that valproic acid could activate AMPK in mouse and human liver cells in a dose-dependent way.
Knowing that valproic acid is extensively processed by cytochrome P450 enzymes, the research team added a cytochrome P450 inhibitor to mouse and human liver cells and found that AMPK was no longer activated.
This suggested that the byproducts of valproic acid, as opposed to valproic acid itself, were the molecules activating AMPK. To test this theory, they added four chemically modified versions of the drug to the cells and found that the derivatives were able to activate AMPK without valproic acid. In fact, they achieved higher activation of AMPK at one-fortieth the concentration.
To assess the uptake and breakdown of valproic acid in living organisms, they gave the drug to obese mice with high blood sugar levels, fatty livers and rapid weight gain.
Treated mice showed decreased blood sugar levels, decreases in the size and the fat accumulation of their livers, and a stabilization of weight - rather than the continued weight gain experienced by untreated mice.
The research has been published in the journal Molecular Pharmacology.