AJP - Endocrinology and Metabolism, Vol 247, Issue 1 111-E117, Copyright © 1984 by American Physiological Society
Fetal fuels. VII. Ketone bodies inhibit synthesis of purines in fetal rat brain
G. E. Shambaugh 3rd, M. C. Angulo and R. R. Koehler
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.
