Myo-inositol monophosphatase: diverse effects of lithium, carbamazepine, and valproate.
The therapeutic molecular sites of action for the mood-stabilizing medications are unknown. Myo-inositol monophosphatase (E.C. 3.1.3.25) is a major enzyme of the inositol signaling system that has previously been shown to be inhibited by clinically relevant concentrations of lithium, implicating this enzyme as a potential therapeutic site of action in manic-depressive disorder. Inhibition of myo-inositol monophosphatase (IMPase), which converts myo-inositol monophosphates to myo-inositol, results in increased levels of myo-inositol monophosphates and decreased myo-inositol available for the resynthesis of inositol phospholipids. In addition to lithium, carbamazepine and valproate are also used medically to treat manic-depressive disorder. It is of considerable interest to determine whether inhibition of IMPase activity is a common unifying mechanism for mood-stabilizing medications. Using a partially purified myo-inositol monophosphatase preparation derived from bovine brain, we examined the effects of lithium, carbamazepine, and valproate on the IMPase reaction. These results demonstrate that (1) lithium inhibited IMPase activity in the low millimolar range, (2) carbamazepine stimulated the IMPase reaction beginning in the low-micromolar range, and (3) valproate did not demonstrate any stimulation or inhibition of IMPase. We conclude that inhibition of IMPase is not a common neurochemical mechanism for mood-stabilizing medications.
Vadnal
R
R
Veterans Affairs Medical Center, Psychiatry Service, Molecular Neuroscience Laboratory, Louisville, KY 40206, USA.
Parthasarathy
R
R
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002118:Calcium / Q000494:pharmacology; D002220:Carbamazepine / Q000494:pharmacology*; D002417:Cattle; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008094:Lithium / Q000494:pharmacology*; D008274:Magnesium / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D002220:Carbamazepine; D014635:Valproic Acid; D008094:Lithium; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; D008274:Magnesium; D002118:Calcium