Molecular cloning of a novel isoform of diphosphoinositol polyphosphate phosphohydrolase: a potential target of lithium therapy.

The mechanisms underlying the therapeutic effects of lithium are largely unknown but may involve progressive adaptive alterations at the level of gene expression. Using differential display PCR, we identify a novel cDNA fragment, the expression of which was increased in the rat frontal cortex after 5 weeks of lithium administration. A full-length cDNA (2954-nt) was cloned by arrayed cDNA library screening, and sequencing of the clone revealed an open reading frame of 537-bp encoding a 179-residue protein. Amino acid sequence comparisons revealed that our clone is a member of the Nudix hydrolase family, with the highest percentage of homology (95%) being with a subtype of human diphosphoinositol polyphosphate phosphohydrolase, hDIPP2. Northern blot analysis revealed that chronic lithium treatment significantly increased rDIPP2 mRNA levels in frontal cortex, but not in hippocampus, midbrain, and cerebellum. The effect of lithium on rDIPP2 mRNA expression was not shared by two other anticonvulsant mood stabilizers, carbamazepine and valproate. Time-course studies showed that 1-week of lithium had no effect on rDIPP2 mRNA abundance in the frontal cortex. Our results suggest that DIPP2 may represent a biologically relevant target of lithium therapy, further supporting the notion that abnormalities in inositol phosphate metabolism may be significant in the pathophysiology and pharmacotherapy of bipolar disorder.

Obesity and precursor availability affect urinary catecholamine metabolite production in women.

The effect of obesity and tyrosine (tyr) supplements on catecholamine metabolism in 12 normal weight and nine obese adult women was studied. Protein intake was maintained at 1.4 g protein/kg fat-free mass daily for 4 days with tyr added (0.26 g/kg fat-free mass) to the liquid diet on the last 2 days. In the 12 normal subjects, but not the obese, base-line urinary excretion of the norepinephrine metabolite, 3-methoxy-4-hydroxy phenylethyleneglycol was related to body fat whereas excretion of the norepinephrine metabolite vanilmandelic acid was related to fat-free mass and to total energy intake. Normal subjects responded to tyr with elevations in plasma tyr/neutral amino acid, plasma 3-methoxy-4-hydroxy phenylethyleneglycol, urinary vanilmandelic acid, and homovanillic acid, a dopamine metabolite, but not the norepinephrine metabolite, dihydroxy phenylethyleneglycol. The obese showed no increase in plasma or urinary 3-methoxy-4-hydroxy phenylethyleneglycol during tyr supplementation, although vanilmandelic acid and homovanillic acid increased. We conclude that urinary catecholamine metabolite production is related to body composition and to tyr intake in normal weight women. These relationships however, are altered in the obese, suggesting an association of obesity with abnormal catecholamine metabolism.