On the Mechanism of Induction of Hepatic Adenosine Triphosphate Deficiency by Ethionine

Abstract

Abstract A method is described for the quantitative determination of S-adenosylethionine (AEt) in perchloric acid extracts of liver. The administration of ethionine to female rats is followed by the rapid accumulation of AEt in the liver. The concentration of AEt increases with increasing doses of ethionine up to about 0.25 to 0.35 mg per g of body weight. The AEt concentration remains at a maximum level for at least 24 hours after a single injection of ethionine. The concentration of free ethionine in the liver and blood is sufficiently high to account for this persistence of maximal AEt levels over this period of time. A close inverse relationship has been found between the concentration of adenosine triphosphate and AEt when measured as a function of time after injection of ethionine. However, a discrepancy exists between the concentrations of ATP and AEt when measured as a function of the dose of ethionine. A maximum liver concentration of AEt is obtained at a dosage level of ethionine which induces only a moderate decrease in ATP concentration. The ATP level continues to fall as the amount of ethionine administered is increased above this level. The basis for this discrepancy has been studied and found to be a progressive inhibition of synthesis of adenine nucleotides de novo with large doses of ethionine associated with the decreasing levels of ATP. The data concerning the various effects of ethionine upon the concentrations of hepatic AEt and ATP and in the induction of various biochemical lesions are consistent with the hypothesis that the primary effect of ethionine is to trap adenosine as AEt by reacting with ATP. With low doses of ethionine, the trapping effect is largely compensated for by a large increase in the rate of synthesis of adenosine monophosphate de novo. With increasingly larger doses of ethionine, the rate of trapping exceeds the rate of synthesis de novo with a resultant decrease in the concentration of adenine nucleotides including ATP. This, in turn, further compromises the new formation of AMP, leading to a progressive decrease in ATP concentration. A new steady state is established at a low level of ATP. During this steady state, AEt is not stable but is continuously broken down and resynthesized. The administration of methionine several hours after ethionine inhibits the further synthesis of AEt, thus allowing the partial resynthesis of ATP from adenosine liberated during transethylation from AEt. This accounts for the partial reversal of those biochemical lesions resulting from the decrease in ATP such as inhibition of protein and ribonucleic acid synthesis and accumulation of excess triglyceride in the liver (fatty liver). The biochemical and structural changes in the liver induced by ethionine offer an interesting example of biochemical lesions induced primarily by lethal synthesis, as enunciated by Peters.