COMPARATIVE-STUDY OF THE CYTOLOGICAL ASPECTS OF THE MODE OF ACTION OFDESTRUXINS AND OTHER PEPTIDIC FUNGAL METABOLITES ON TARGET EPITHELIAL-CELLS

The cytopathological effects of cyclic fungal peptides, destruzins (dt xs) A and E, Cyclosporin A, and Linear peptaibols efrapeptins (=tolypi n), on epithelial cells were studied by in vitro experiments with prep arations of insect organs. The treatment of Malpighian tubules and mid gut revealed the induction by dtx E of the formation of vesicles on mi crovilli of Malpighian cells and on the apical surface of midgut cells . This morphological alteration of the brush border was a Ca2+-depende nt process, very strongly inhibited in Ca2+-free medium or when a comb ined treatment with cadmium chloride + dtx E was applied. However, cad mium chloride did not inhibit all the cytotoxic effects of dtx E. The ability to trigger the formation of vesicular structures is a property of biologically active dtxs, the inducing capacity showing, however, a decreasing intensity from dtx E to dtx A and dtx B. On the contrary, the other peptides, Cyclosporin A and efrapeptins, did not induce the formation of vesicles. The most obvious intracellular alterations con sist of a pycnosis of the nucleus, and in changes of mitochondria, the contents of which show a decrease in density and are comparable to th ose observed in vivo. If mitochondria are target organelles for the th ree different types of toxins tested, the structural changes induced a t this level were specific for dtxs, Cyclosporin A, and efrapeptins, r espectively. The cytological data obtained strongly suggested that dtx s have a unique mode of action among fungal peptides and do not act ma inly as ionophores, inducing the formation of pores in cellular membra nes, or as mitochondrial ATPase inhibitors. (C) 1996 Academic Press, I nc.