DISPOSITION OF HOMOCYSTEINE IN RAT HEPATOCYTES AND IN NONTRANSFORMED AND MALIGNANT MOUSE EMBRYO FIBROBLASTS FOLLOWING EXPOSURE TO INHIBITORS OF S-ADENOSYLHOMOCYSTEINE CATABOLISM

Abstract

5-Adenosylhomocysteine (AdoHcy) is catabolized to adenosine and homocysteine through the action of AdoHcy hydrolase, and this reaction is the only known source of L-homocysteine in vertebates. The disposition of endogenously formed L-homocysteine was investigated in isolated rat hepatocyte and nontransformed and malignant C3H/10T 1/2 mouse embyro fibroblasts exposed to 3-deazaaristeromycin or D-eritadenine, compounds which are potent inhibitors of AdoHcy hydrolase. Cells in suspension release large amounts of L-homocysteine into the extracellular medium whereas small amounts are retained within the intracellular compartment. The L-homocysteine egress is inhibited by 3-deazaaristeromycin or D-eritadenine in a manner which closely parallels the inhibitory effect on AdoHcy catabolism, suggesting the L-homocysteine egress may be coupled to its formation from AdoHcy. In liver cells, the accumulation of AdoHcy exceeded the inhibition of L-homocysteine egress, whereas in the fibroblasts inhibition of egrees equalled the accumulation of AdoHcy. Inhbition of ADoHcy catabolism was associated with an increase in both free and protein bound L-homocysteine in liver cells, whereas depletion of intracellular L-homocysteine occurred in the mouse embryo fibroblasts under these conditions. These data suggest that some properties of nucleoside analogues may be related to their effects on L-homocysteine metabolism. Furthermore, L-homocysteine is exported into the extracellular medium in proportion to the formation from AdoHcy, and extracellular L-homocysteine may be a measure of the balance between L-homocysteine formation and utilization.