Methanethiol (CH3SH) has been implicated in the pathogenesis of hepatic coma. Studies are presented to identify the possible biochemical basis of anesthesia-like effects of methanethiol and those features which distinguish such effects from common anesthetics and may represent the basis of its toxicity. CH3SH was found to stabilize erythrocyte membranes against hypotonic hemolysis at relatively low concentrations. At 37°C the AH25 value for human erythrocyte antihemolysis was observed at a concentration of 0.34 μmol of CH3SH bound per mg of erythrocyte protein. Similar results were obtained with rat erythrocytes. This property of CH3SH is in common with other anesthetic agents. Anesthetic agents also inhibit the membrane-associated Na+,K+-adenosine triphosphatase (ATPase); however, for effective and nontoxic agents of this type the inhibition of ATPase activity is elicited at concentrations which are at least an order of magnitude higher than those which influence the membrane stability characterized by the antihemolysis effect. CH3SH was also found to inhibit the membrane Na+,K+-ATPase activity. The I25 value for the inhibition of human erythrocyte ATPase activity was obtained at CH3SH concentration of 0.12 mM which corresponded to 0.3 μmol of CH3SAH bound per mg of erythrocyte membrane protein. Rat erythrocyte membrane ATPase was somewhat more sensitive to CH3SH. In all cases the binding of CH3SH to erythrocytes occurred primarly on the membrane. These results indicate that no differential exists with respect to the dose-response of these two activities associated with human erythrocyte membrane. Thus, stabilization of erythrocyte membrane by CH3SH may reflect its action as a comatogenic agent; however, the development of potent inhibition of membrane Na+,K+-ATPase at similar concentrations which are associated with membrane stabilization hints at a possible additional contributing mechanism in the toxicity of CH3SH in vivo and hence in the pathophysiology of hepatic coma.
|Original language||English (US)|
|Number of pages||6|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Jan 1 1984|