PROTECTION BY NARINGIN AND SOME OTHER FLAVONOIDS OF HEPATOCYTIC AUTOPHAGY AND ENDOCYTOSIS AGAINST INHIBITION BY OKADAIC ACID

被引:66
作者
GORDON, PB [1 ]
HOLEN, I [1 ]
SEGLEN, PO [1 ]
机构
[1] NORWEGIAN RADIUM HOSP, INST CANC RES, DEPT TISSUE CULTURE, N-0310 OSLO 3, NORWAY
关键词
D O I
10.1074/jbc.270.11.5830
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 [H-3]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 mu M). Naringin, the most potent okadaic acid-antagonistic flavonoid, gave half-maximal protection at 5 mu M and maximal effect at 100 mu M. 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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页码:5830 / 5838
页数:9
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