Aflatoxin B-1 is an inhibitor of cyclic nucleotide phosphodiesterase activity

Aflatoxin B-1 (AFB(1)) action on cyclic nucleotide phosphodiesterase (PDE) activity has been tested on tissue extracts of various organs. In the prese nce of 100 mu M AFB(1) a significant inhibition of cAMP and cGMP hydrolytic activity is observed in all tested tissue extracts. However, cGMP hydrolyt ic activity appears more sensitive to AFB(1) inhibition than cAMP hydrolyti c activity and a considerably higher inhibition is observed in lung and spl een, than in liver, brain, kidney, and heart. When cGMP is used as substrat e, the inhibitory response reaches 72% in lung and spleen extracts. We have also tested AFB(1) effects on lung and liver PDE activity peaks separated by DEAE-cellulose chromatography. These data confirm the poor sensitivity t o the toxin of all PDE activities present in liver, while the lung peak (wh ere PDE V in present) shows a higher sensitivity to AFB(1). In order to est ablish whether PDE V is in fact more sensitive to AFB(1), we have used mous e neuroblastoma cells, in which cGMP hydrolytic activity has been shown to be due to PDE V only. In this case, the calculated IC50 is 24 mu M and Dixo n plot analysis shows a competitive inhibitory effect with a Ki of 16.7 mu M. We have also used aflatoxin B-2 and M-2, and they proved to be much less effective than AFB(1): AFB(2) inhibits PDE V with an IC50 of 117 mu M, whi le AFM(2) does not show any effect. These results provide the first evidenc e of a competitive inhibition of AFB(1) on an enzymatic activity and sugges t that an alteration of cellular cyclic nucleotide levels may play a role i n the mechanism of aflatoxin action. All rights reserved. (C) 1999 Elsevier Science Inc. All rights reserved.