Phosphorylation of cytochrome-P-450-dependent monooxygenase components |
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Authors: | W Pyerin C R Wolf V Kinzel D Kübler F Oesch |
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Institution: | 1Cancer Research Center, Institute of Experimental Pathology D-6900 Heidelberg, FRG
2Institute of Pharmacology, University of Mainz D-6500 Mainz, FRG |
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Abstract: | Most chemical carcinogens require activation by polysubstratemonooxygenase. The phosphorylation of essential components ofthis cytochrome P-450 monooxygenase system, isolated from rabbitliver microsomes, cytochrome P-450 (LM2) and cytochrome reductase,was tested using two different protein kinases. One of the kinases,a cyclic AMP-independent phosvitin kinase (kinase P), was inactivein all systems tested. However, the catalytic subunit of a cyclicAMP-dependent protein kinase (kinase C) catalyzed phosphorylgroup transfer to both proteins, but to different extents. CytochromeP-450 was phosphorylated when added as sole component and alsowhen in the presence of P-450 reductase and phosphatidylcholine.In contrast, the weak phosphorylation of P-450 reductase wasreduced considerably in a complete reconstituted system containingP-450 and phosphatidylcholine. The inclusion of kinase P didnot alter these results which excludes the possibility thatthese kinases participate in a sequential phosphorylation mechanism.The monooxygenase constituents themselves were without kinaseactivity. When hepatic microsomes were isolated in presenceof the phosphatase inhibitor sodium fluoride no significantchange in monooxygenase (7-ethoxycoumarin O-deethylation) activitywas observed, whilst after preincubation with either acid oralkaline phosphatase a significant reduction in monooxygenaseactivity was measured. Thus, cytochrome P-450 (LM2) is phosphorylatableby protein kinase C and the catalytic activity of polysubstratemonooxygenase decreases after preincubation of microsomes withphosphatases. |
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