AJP - Endocrinology and Metabolism, Vol 243, Issue 3 234-E239, Copyright © 1982 by American Physiological Society
Fetal fuels. V. Ketone bodies inhibit pyrimidine biosynthesis in fetal rat brain
S. Bhasin and G. E. Shambaugh 3rd
Ketonemic states complicating late pregnancy are accompanied by lower brain
weights in the newborn. Potential mechanisms whereby ketone bodies might
inhibit cell proliferation were therefore examined in the fetal rat brain
slice by measuring their impact on the de novo pathway for pyrimidine
biosynthesis. DL-beta-hydroxybutyrate (10.8 mM) and acetoacetate (5.4 mM)
were both found to diminish the incorporation of NaH14CO3 into [14C]UMP by
30%. This effect was similar in fetal tissues from fed and 48-h starved
mothers. Graded concentrations of DL-beta-hydroxybutyrate (1.4-43.2 mM)
resulted in a progressive inhibition that could not be explained either by
isotope dilution consequent to ketone body oxidation or by a generalized
inhibition of protein synthesis. The inhibition was not reversed with 10 mM
glutamine, the principal nitrogen substrate for de novo biosynthesis of
pyrimidines. When the conversion of orotic acid into UMP was blocked with
6-azauridine, DL-beta-hydroxybutyrate (10.8 mM) inhibited the incorporation
of NaH14CO3 into orotic acid by 28%. By contrast, maximally inhibitory
concentrations of this ketone body (43.2 mM) had no effect on the
incorporation of [6-14C]orotic acid into [14C]UMP. Is is concluded that
ketone bodies inhibit the de novo biosynthesis of pyrimidines in fetal
brain slices and that they do so at a site proximal to orotic acid
formation.
