Morphologic and Metabolic Alterations in Hepatic Cell Nucleoli Induced by Varying Doses of Actinomycin D¹ Free

The effect of varying doses of actinomycin D on the nucleolar structure and RNA metabolism of hepatic parenchymal cells of the rat has been investigated. Maximal dissociation of the nucleolar components as well as maximal inhibition of RNA synthesis was seen at dose levels of the drug above 0.75 μg/gm body weight. Some gradation in the morphologic effect was seen, particularly at dose levels below 0.3 μg/gm body weight. Below this level portions of the nucleolonema persist, particularly in the periphery of the nucleolar mass, all nucleoli being affected. A dose of 0.01 μg/gm body weight produces no alteration in synthetic ability and does not produce a discernible morphologic change. Although breakdown of newly synthesized RNA is documented, and this too appears to be dose dependent, it was not possible to separate this effect from inhibition of synthesis. The exact mechanism of the morphologic alteration is still unknown. However, it is unlikely that inhibition of RNA synthesis or failure to transfer newly synthesized RNA from nucleus to cytoplasm are responsible, since regeneration of the nucleolus takes place while marked inhibition of synthesis persists and because ethionine, which produces inhibition of synthesis and prevents transfer to a similar degree, does not induce this morphologic change. Although enhanced breakdown of newly synthesized RNA remains a possible mechanism, it is postulated that the physical combination of the actinomycin molecules with the DNA molecules governing nucleolus synthesis may be more important than inhibition of synthesis, failure to transfer, or breakdown of newly synthesized RNA per se in producing this change.