The Hepatocyte Protein Synthesis Defect Induced by Galactosamine Involves Hypomethylation of Ribosomal Rna

Abstract

D–galactosamine produces an early defect in protein synthesis, independent of its effects on RNA synthcsis. Here we show that the defect in protein synthesis is inherent in purified ribosomal subunits in vitro. Furthere, galactosamine treatment is associated with an 85% decrease in methylation of ribosomal RNA, involving all sites (2′–0–ronpse and base positions), intact ribosomes from galactosamine–treated animals can be methylated to a greater extent than control ribosomes and in vitro methylation restores their funtional capacity. Statistical analyes of these data, along with those with a number of other hepatotoxins, reveal a correlation coefficent of r = 0.95 (p < 0.003) between protein synthetic capacity and ribosomal RNA methylaiton, and linear regression accounts for more than 90% of the observed variation. In contrast, no relationship was found between nucleolar RNA methylation and protein synthetic capacity. A relationship of borderline statistical significance was found between messenger RNA methylaiton and protein synthetic capacity, but it does not appear consistent with results obtained after CCI₄ intoxication. These results lend strong support ot the notion that methylation status of ribosomal RNA is an important control for protein synthesis in quiscent hepatocytes and that net hypomethylation is a common responses to such divergent hepatotoxins as CCI₄, ethionine and d–galactosamine. (Hepatology 1990;11:428-434.)