Bhasin S, Shambaugh G E
Am J Physiol. 1982 Sep;243(3):E234-9. doi: 10.1152/ajpendo.1982.243.3.E234.
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.
妊娠晚期并发酮血症状态时，新生儿脑重量较低。因此，通过测量酮体对嘧啶生物合成从头途径的影响，在胎鼠脑切片中研究了酮体可能抑制细胞增殖的潜在机制。发现DL-β-羟基丁酸（10.8 mM）和乙酰乙酸（5.4 mM）均使NaH14CO3掺入[14C]UMP的量减少30%。在喂食和饥饿48小时的母鼠的胎儿组织中，这种作用相似。不同浓度的DL-β-羟基丁酸（1.4 - 43.2 mM）导致逐渐抑制，这既不能用酮体氧化导致的同位素稀释来解释，也不能用蛋白质合成的普遍抑制来解释。用10 mM谷氨酰胺（嘧啶从头生物合成的主要氮底物）不能逆转这种抑制作用。当用6-氮尿苷阻断乳清酸向UMP的转化时，DL-β-羟基丁酸（10.8 mM）使NaH14CO3掺入乳清酸的量减少28%。相比之下，这种酮体的最大抑制浓度（43.2 mM）对[6-14C]乳清酸掺入[14C]UMP没有影响。结论是酮体抑制胎鼠脑切片中嘧啶的从头生物合成，并且它们在接近乳清酸形成的位点发挥作用。
