Ethanol Inhibition of Rabbit Reticulocyte Haem Synthesis at the Level of δ‐Aminolaevulinic Acid Synthetase

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Abstract
Ethanol inhibition of rabbit reticulocyte protein synthesis occurs as a result of a decrease in heme synthesis. The inhibitory site of ethanol was localized on the heme biosynthetic pathway. Ethanol (0.05-0.15 M) inhibition of reticulocyte protein synthesis was prevented by simultaneous incubation with 0.025-1 mM .delta.-aminolevulinic acid (ALA). Ethanol inhibited 14C-glycine and 14C-ALA incorporation into heme. The extent of heme formation with 14C-ALA as substrate in the presence of ethanol was still equal to that when 14C-glycine was used. Ethanol apparently inhibits the heme synthetic pathway at several loci, but the decrease in heme synthesis, responsible for the decrease in protein synthesis, may be due to the inhibition at the rate-limiting enzyme, .delta.-aminolevulinic acid synthetase (ALA-S). To confirm this, ALA-S activity was then directly measured in intact reticulocytes, and ethanol indeed inhibited its activity. The inhibition of ALA-S was prevented by 10-4 M dibutyryl cyclic AMP (db cAMP) or theophylline, agents which elevate intracellular cAMP and prevent and reverse ethanol inhibition of heme and protein synthesis. It appears that cAMP protects against ethanol toxicity by preventing inhibition of ALA-S.

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