Ethanol inhibition of reticulocyte protein synthesis: the role of haem.
Ethanol, in concentrations of 0.05-0.8 M, inhibited intact human and rabbit reticulocyte protein synthesis in the presence of iron-transferrin for endogenous haem synthesis. Associated with this effect there was a conversion of polyribosomes to monoribosomes and a decreased incorporation of radioactive leucine into nascent globin chains. When physiological levels of ethanol (0.05-0.1 M) were used, these effects were prevented by incubation with 50 muM haemin and reversed by removing the alcohol and reincubating with iron-transferrin or haemin. The polyribosomal disaggregation was also prevented by stopping ribosomal movement with 5 mM cycloheximide. Neither ATP nor GSH levels were altered in the presence of ethanol. When non-physiological levels of 0.8 M ethanol were used, haemin did not prevent the inhibition of protein synthesis. Likewise, in the rabbit reticulocyte cell-free lysate system containing haemin inhibition was noted at concentrations greater than 0.05 M ethanol. The polyribosomal disaggregation in reticulocytes incubated with 0.8 M ethanol was associated with decreased dissociation of monoribosomes into subunits. Similarly, when ribosomes were directly suspended cell-free in 0.1 or 0.8 M ethanol there was a decreased percentage of subunits. These results indicate that physiological concentrations of ethanol inhibit initiation of reticulocyte protein synthesis secondary to a block in haem synthesis. When intact cells are exposed to high non-physiological concentrations of ethanol the inhibition is secondary to decreased ribosomal dissociation. The cell-free lysate inhibition is also through this effect on ribosomal dissociation. This study supports the view that alcohol is a direct toxin to developing red cell precursors via its effect on mitochondrial haem synthesis. The physiological role of the decreased dissociation of monoribosomes into subunits is not yet clear.
D000079:Acetaldehyde / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors; D000818:Animals; D000431:Ethanol / Q000494:pharmacology*; D005914:Globins / Q000096:biosynthesis; D005978:Glutathione / Q000037:antagonists & inhibitors; D006410:Hematopoiesis / Q000187:drug effects; D006418:Heme / Q000502:physiology*; D006427:Hemin / Q000378:metabolism; D006801:Humans; D011132:Polyribosomes / Q000187:drug effects; D011817:Rabbits; D012156:Reticulocytes / Q000187:drug effects*; D012270:Ribosomes / Q000187:drug effects; D014168:Transferrin / Q000378:metabolism
D014168:Transferrin; D000431:Ethanol; D006418:Heme; D006427:Hemin; D000255:Adenosine Triphosphate; D005914:Globins; D005978:Glutathione; D000079:Acetaldehyde