Control of nucleic acid and protein synthesis in developing brain, kidney, and heart of the neonatal rat: effects of alpha-difluoromethylornithine, a specific, irreversible inhibitor of ornithine decarboxylase.

Ornithine decarboxylase (ODC) and the polyamines are thought to play a role in maturation of mammalian tissues. Daily postnatal administration of alpha-difluoromethylornithine (DFMO, a specific inhibitor of ODC) to newborn rats caused organ-specific deficits in tissue weight gain, with brain and kidney as the major targets. Subnormal organ weights were associated with deficits in the levels of nucleic acids and proteins in the affected tissues, and examination of the synthetic rates of DNA ([3H]thymidine incorporation), RNA ([3H]uridine incorporation) and protein ([14C]leucine incorporation) confirmed that macromolecule synthesis was inhibited in DFMO-treated pups. The time of onset of effect of DFMO on the synthesis of nucleic acids and proteins was the same as that reported for depletion of polyamines by this treatment. Potential adverse effects of DFMO on cell survival were also assessed by labeling DNA with [3H]thymidine on day 3 and examining retention of label 12 days later; DFMO did not cause an increase in cell death. In contrast to the sensitivity of brain and kidney to postnatally administered DFMO, development of cardiac tissue was relatively resistant to growth inhibition despite polyamine depletion. The organ specificity of effect of DFMO results, in part, from the different timetables for cellular events in tissue development displayed by each organ type; administration of DFMO earlier in development (during days 15 to 17 of gestation) did produce deficiencies in cardiac growth and nucleic acid levels similar to those which had been seen for brain and kidney. These data support the view that polyamines play a key role in cell replication, differentiation and growth during critical periods of mammalian organ development through their regulation of DNA, RNA, and protein synthesis.

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Author Theodore Alan Slotkin Pharmacology & Cancer Biology