HATANAKA Yasumaru Toyama Medical Pharmaceutical University, Research Institute for Wakan-Yaku, Ass, 和漢薬研究所, 助教授 (30111181)
OHTA Tetsuo Kanazawa University, Fac.Medicine.Associate Professor, 医学部・附属病院, 講師 (40194170)
YOKOYAMA Ken Kanazawa University, Fac.Pharmaceut.Sci., Assistant Professor, 薬学部, 助手 (70271377)
ARAI Kunizo Kanazawa University, Fac.Pharmaceut.Sci., Assistant Professor, 薬学部, 助手 (50126562)
|Budget Amount *help
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 1998: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1997: ¥2,800,000 (Direct Cost: ¥2,800,000)
In this research project, we have studied the machanism of (1) inhibition of cell growth, (2) induction of cell differentiation, and (3) induction of apoptosis, by V-ATPase inhibitors like bafilomycins, prodigiosins and destruxins, as well as the mechanims of inhibition of proton translocation by these inhibitors.
We found (1) that both destrauxin-B and -E inhibited lysosomal proton pump, but only destruxin-E induced induced neurite out growth (NOG) of PC12 cells., (2) that prodigisins uncoupled various proton pump activities due to their H ^+ /Cl symport activity, (3) that prodigiosins, like bafilomycin A ^<1'> induced neurite out growth (NOG), and (4) that the prodigiosin-induced NOG, like bafolomycin-induced one, required de novo synthesis of new messenger RNA as well as protein synthesis, was sensitive to the inhibitors of MAP kinases, serine/threonine phosphatases, tyr-kinases, tyr-phosphatases, calmidulin and phospholipase A ^<2' > but resistant to inhibitors of trk tyrosine kinase and protein kinase A.BE-18591, a tambjamine group antibiotics, also behaved as H ^+ /CU symporters and inhibited hog gastric proton pump, inhibit *cid secretion by gastric parietal cells, inhibited osteoclast differentiation, suppressed proliferation of immune lymphocytes, and induced both NOG and apoptosis, suggesting that the variety of biological activities displayed by these H ^+ /C1 symporters may be due to their H ^+ /C1 symport activity. However, tetrapyrrole, another H ^+ /CV symporter, did not induced NOG.
From these results, we conclud that the effect of V-ATPase inhibitors on the intracellular pH does not participate in the variety of biological activities (including induction of NOG) displayed by these compounds.