Forskolin attenuates doxorubicin-induced accumulation of asymmetric dimethylarginine and s-adenosylhomocysteine via methyltransferase activity in leukemic monocytes

Possible signal pathway by which forskolin regulates arginine methylation. Forskolin prevents doxorubicin-induced methyltransferase activity which mitigates biosynthesis of ADMA and SAH, the intermediate products of protein methylation. ADMA is an endogenous inhibitor of eNOS which catalyses the formation of nitric oxide. Hence, an increase in intracellular or circulating ADMA concentration leads to eNOS uncoupling and endothelial dysfunction. Such an inhibitory effect of FSK has the potential to prevent eNOS uncoupling under DOX insult. (+) - potentiation; - inhibition; 1 - Methylation pathway; 2 - Transmethylation pathway; 3 - Remethylation pathway; ADMA - asymmetric dimethylarginine; CVD - cardiovascular disease; DDAH - Dimethylarginine dimethylaminohydrolase; DOX - doxorubicin; ED - endothelial dysfunction; eNOS - endothelial nitric oxide; L-cit - L-citrulline; L-NMMA - L-N-monomethylarginine; MAT - methionine adenosyltransferase; MT - methyltransferases; MS - methionine synthase; Met - S-methionine; NO - nitric oxide; SAM - S-adenosylmethionine; SAH - S-adenosylhomocysteine; SAHH - S-adenosylhomocysteine hydrolase; FSK - Forskolin; HCY - homocysteine; L-arg - L-arginine88