Yeast bioassay for identification of inositol depleting compounds.
Bipolar affective disorder is a chronic, severe, debilitating illness affecting 1-2% of the population. Valproate, along with lithium and carbamazepine, are the only drugs for which long-term efficacy has been established. However, these drugs are ineffective for, and not well tolerated by, a large number of patients and are also associated with teratogenicity and reproductive defects. Therefore, there is a substantial need to develop more effective anti-bipolar drugs. We have previously shown that valproate, like lithium, decreases intracellular inositol, which supports the inositol depletion hypothesis. We employed inositol depletion in yeast as a screening tool to identify potential new anti-bipolar medications. We show here that hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, ethylhexanoate, and methyloctanoate decrease intracellular inositol levels and increase the expression of INO1, the gene encoding myo-inositol-3-phosphate synthase (MIPS). Similar to valproate, these inositol-depleting carboxylic acids inhibited MIPS indirectly. A correlation was shown between cell growth inhibition and the increase in INO1 expression by the carboxylic acids, factors that were reversed in the presence of inositol. Inositol depletion in yeast may be exploited as an easy and inexpensive screening test for potential new inositol depleting anti-bipolar drugs.
Ding
Daobin
D
Department of Biological Sciences, Wayne State University, Detroit, MI 48202, USA.
Shi
Yihui
Y
Shaltiel
Galit
G
Azab
Abed N
AN
Pullumbi
Ervin
E
Campbell
Adam
A
Mehta
Dhara V
DV
Agam
Galila
G
Greenberg
Miriam L
ML
D000927:Anticonvulsants / Q000009:adverse effects*; D018692:Antimanic Agents / Q000009:adverse effects*; D001681:Biological Assay; D001714:Bipolar Disorder / Q000188:drug therapy*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002264:Carboxylic Acids / Q000009:adverse effects*; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D006801:Humans; D007294:Inositol / Q000172:deficiency* / Q000378:metabolism*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D016651:Lithium Carbonate / Q000009:adverse effects*; D007296:Myo-Inositol-1-Phosphate Synthase / Q000187:drug effects / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000187:drug effects / Q000235:genetics; D014635:Valproic Acid / Q000009:adverse effects*; D015003:Yeasts / Q000502:physiology*
D000927:Anticonvulsants; D018692:Antimanic Agents; D002264:Carboxylic Acids; D029701:Saccharomyces cerevisiae Proteins; D016651:Lithium Carbonate; D007294:Inositol; D014635:Valproic Acid; C519641:INO1 protein, S cerevisiae; D007296:Myo-Inositol-1-Phosphate Synthase