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(Received for publication, October 5, 1994) In isolated rat hepatocytes, the protein phosphatase inhibitor
okadaic acid exerts a strong inhibitory effect on autophagy, which can
be partially overcome by certain protein kinase inhibitors like the
isoflavone genistein. To see if other, more specific okadaic acid
antagonists could be found among the flavonoids, 55 different
flavonoids were tested for their effect on okadaic acid-inhibited
autophagy, measured as the sequestration of electroinjected
[
Volume 270,
Number 11,
Issue of March 17, 1995 pp. 5830-5838
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
H]raffinose. Naringin (naringenin
7-hesperidoside) and several other flavanone and flavone glycosides
(prunin, neoeriocitrin, neohesperidin, apiin, rhoifolin, kaempferol
3-rutinoside) offered virtually complete protection against the
autophagy-inhibitory effect of okadaic acid. Unlike genistein, these
compounds had little or no autophagy-inhibitory effect of their own.
Their innocuousness appeared to be related to glycosylation, because
the corresponding aglycones (naringenin, eriodictyol, hesperetin,
apigenin, kaempferol) were all inhibitory, in particular apigenin (80%
inhibition at 100 µM). Naringin, the most potent okadaic
acid-antagonistic flavonoid, gave half-maximal protection at 5
µM and maximal effect at 100 µM. Naringin
also prevented the okadaic acid-induced inhibition of endogenous,
autophagic lysosomal protein degradation and of receptor-mediated
asialoglycoprotein uptake and degradation. Naringin and other okadaic
acid-antagonistic flavonoids may be useful tools in the study of
intracellular protein phosphorylation and could have potential
therapeutic value as protectants against pathological
hyperphosphorylations, environmental toxins, or side effects of
chemotherapeutic drugs.
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