Aflatoxin B1 is an inhibitor of cyclic nucleotide phosphodiesterase activity

Aflatoxin B₁ (AFB₁) action on cyclic nucleotide phosphodiesterase (PDE) activity has been tested on tissue extracts of various organs. In the presence of 100 μM AFB₁ a significant inhibition of cAMP and cGMP hydrolytic activity is observed in all tested tissue extracts. However, cGMP hydrolytic activity appears more sensitive to AFB₁ inhibition than cAMP hydrolytic activity and a considerably higher inhibition is observed in lung and spleen, than in liver, brain, kidney, and heart. When cGMP is used as substrate, the inhibitory response reaches 72% in lung and spleen extracts. We have also tested AFB₁ effects on lung and liver PDE activity peaks separated by DEAE-cellulose chromatography. These data confirm the poor sensitivity to the toxin of all PDE activities present in liver, while the lung peak (where PDE V in present) shows a higher sensitivity to AFB₁. In order to establish whether PDE V is in fact more sensitive to AFB₁, we have used mouse 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 μM and Dixon plot analysis shows a competitive inhibitory effect with a Ki of 16.7 μM. We have also used aflatoxin B₂ and M₂, and they proved to be much less effective than AFB₁: AFB₂ inhibits PDE V with an IC₅₀ of 117 μM, while AFM₂ does not show any effect. These results provide the first evidence of a competitive inhibition of AFB₁ on an enzymatic activity and suggest that an alteration of cellular cyclic nucleotide levels may play a role in the mechanism of aflatoxin action. All rights reserved. Copyright (C) 1999 Elsevier Science Inc.