Figure 2.

Putatative mechanisms of autophagy suppression by ethanol. Ethanol metabolism by the three major pathways, alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1) and catalase generates acetaldehyde, which can undergo secondary reactions with malondialdehyde (MDA) to form MAA. In addition, reactive oxygen species (ROS) are generated by CYP2E1 catalysis. Reactive oxidants (ROS) may also contribute to lysosomal damage. The reactive aldehydes are known to form adducts with tubulin and other cytoskeletal elements to block trafficking and movement of autophagic vacuoles and their formation. The combined formation of ROS and acetaldehyde putatively cause upregulation of protein phosphatase 2A (PP2A) and a downregulation of LKB1 and PKC zeta. The latter changes cause inactivation of AMPK, which in turn suppresses autophagy due to up regulation of mTOR (not shown) as described in the text.