Fetal fuels. VII. Ketone bodies inhibit synthesis of purines in fetal rat brain.

Abstract

Maternal starvation in late gestation results in ketonemia and a lowered DNA content in fetal rat brain. Because purines are needed for formation of new RNA and DNA, we examined the de novo pathway for purine biosynthesis in fetal rat brain slices by measuring the incorporation of [14C]formate into [14C]adenine. Maternal starvation days 18-20 resulted in a slight but nonsignificant fall in purine biosynthesis from 0.230 +/- 0.006 to 0.216 +/- 0.006 mumol X g-1 X 2 h-1. Graded concentrations of DL-3-hydroxybutyrate (3OHB) produced a progressive inhibition of formate incorporation in fetal brain slices, and rates of purine biosynthesis in the presence of 5.4 mM 3OHB were significantly lower (P less than 0.01) in fetal brain slices from both fed and starved mothers, i.e., 0.199 +/- 0.006 and 0.189 +/- 0.006 mumol X g-1 X 2 h-1, respectively. Acetoacetate caused an inhibition similar in magnitude to 3OHB. That 3OHB did not act via a protein biosynthetic step was evidenced by unimpaired biosynthesis of purines and sustained 3OHB inhibition in the presence of 1 mM cycloheximide. Unlike the de novo pathway, the salvage pathway measured by incorporation of [8-14C]adenine into labeled nucleotides was not significantly inhibited even by supraphysiological levels of 3OHB (21.6 mM). Serial measurements of the de novo and salvage pathways in neonatal brain slices showed a maintenance of salvage activity during the first 2 wk but a progressive fall in activity of the de novo pathway. Thus ketone bodies could act to restrain the synthesis of purine nucleotide building blocks for new cell formation in fetal but not in neonatal rat brain.