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Posttranslational modifications of the cytochrome P-450 monooxygenase system

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Summary

Two forms of enzymatic posttranslational modifications of the monooxygenase system are described: modification by phosphatase and modification by protein kinase. Phosphatase treatment of microsomes isolated from phenobarbital-pretreated rabbits and rats caused a marked decrease of monooxygenase activity which was paralleled by a comparable decrease of NADPH-cytochrome P-450 reductase activity while the second essential component of the system, cytochrome P-450, remained unaltered. Thus phosphatase attacks monooxygenase via reductase. Protein kinases showed the opposite preference; while cytochrome P-450 was phosphorylated, NADPH-cytochrome P-450 reductase was not. Thus the kinase affects monooxygenase via cytochrome P-450. The phosphorylation of cytochrome P-450 turned out to be a specific reaction observed only with certain cytochrome P-450 isoenzymes and certain protein kinases.

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References

  1. Adesnik M, Atchison M (1985) Genes for cytochrome P-450 and their regulation. CRC Crit Rev Biochem 19:247–305

  2. Cohen P (1982) The role of protein phosphorylation in neural and hormonal control of cellular activity. Nature 296:613–620

  3. Flockhart DA, Corbin JD (1982) Regulatory mechanisms in the control of protein kinases. CRC Crit Rev Biochem 12:133–186

  4. Goodwin CD; Cooper BW, Margolis S (1982) Rat liver cholesterol 7α-hydroxylase; modulation of enzyme activity by changes in phosphorylation state. J Biol Chem 257:3369–4472

  5. Gotoh O, Tagashira Y, Lizuka T, Fujii-Kuriyama Y (1983) Structural characteristics of cytochrome P-450. Possible location of the heme-binding cysteine in determined amino-acid requences. J Biochem 93:807–817

  6. Horn F, Gschwendt M, Marks F (1985) Partial purification and characterization of the calcium-dependent and phospholipiddependent protein kinase C from chick oviduct. Eur J Biochem 148:533–538

  7. Imai Y (1976) The use of 8-aminooctyl sepharose for the separation of some components of the hepatic microsomal electron transfer system. J Biochem 80:267–276

  8. Imai Y, Hashimoto-Yutsudo C, Satake H, Girardin A, Sato R (1980) Multiple forms of cytochrome P-450 purified from liver microsomes of phenobarbital- and 3-methylcholanthrene-pretreated rabbits. J Biochem 88:489–503

  9. Ingelman-Sundberg M, Glaumann H (1980) Incorporation of purified components of the rabbit liver microsomal hydroxylase system into phospholipid vesicles. Biochim Biophys Acta 599:417–435

  10. Jerina DM, Sayer JM, Yagi H, Van Bladeren PJ, Thakker DR, Levin W, Chang RL, Wood AW, Conney AH (1985) Stereo-selective metabolism of polycyclic aromatic hydrocarbons to carcinogenic metabolites. In: Boobis AR, Caldwell J, De Matteris F, Elcombe CR (eds) Microsomes and drug oxidations, Proceedings of the 6th International Symposium, Brighton. Taylor & Francis, London and Philadephia, 310–319

  11. Krebs EG, Beavo JA (1979) Phosphorylation and dephosphorylation of enzymes. Ann Rev Biochem 48:923–959

  12. Kübler D, Gagelmann M, Pyerin W, Kinzel V (1979) Isolation of the catalytic subunits of cyclic AMP-dependent protein kinases from different mammalian tissues on the basis of charge differences of their subunits. Hoppe Seylers Z Physiol Chem 360:1421–1431

  13. Kübler D, Pyerin W, Kinzel V (1982) Protein kinase activity and substrates at the surface of intact HeLa cells. J Biol Chem 257:322–329

  14. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275

  15. Müller R, Schmidt WE, Stier A (1985) The site of cyclic AMP-dependent protein kinase catalyzed phosphorylation of P-450 LM 2. FEBS Lett 187:21–24

  16. Nishizuka Y (1984) The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 308:693–698

  17. Omura T, Sato R (1964) The carbon monoxide-binding pigment of liver microsomes. J Biol Chem 239:2370–2385

  18. Pyerin W, Hecker E (1979) On the biochemical mechanism of tumorigenesis in mouse skin. IX. Interrelation between tumor initiation by 7,12-dimethylbenz(a)anthracene and the activities of epidermal arylhydrocarbon monooxygenase and epoxide hydratase. J Cancer Res Clin Oncol 93:7–30

  19. Pyerin WG, Hecker E (1980) Tumour initiation in mouse skin by 7,12-dimethylbenz(a)anthracene: irrelevance of systemic activation. Cancer Lett 8:317–321

  20. Pyerin WG, Hecker E (1983) Monooxygenase activity of human epithelial cell (HeLa): Comparison of the response to treatment by arylhydrocarbons and diterpene esters. J Cancer Res Clin Oncol 106:71–73

  21. Pyerin W, Gagelmann M, Kübler D, Kinzel V (1979) Catalytic subunit of adenosine cyclic 3′,5′-monophosphate-dependent protein kinase from rat muscle: basic properties and factors influeencing the activity. Z Naturforsch 34c:1186–1194

  22. Pyerin W, Oberender HA, Hecker E (1980) Extent of skin tumour initiation in mice by 7,12-dimethylbenz(a)anthracene and induction of arylhydrocarbon monooxygenase are not causally related. Cancer Lett 10:155–162

  23. Pyerin W, Balbach N, Kübler D, Kinzel V (1981) Protein kinases in HeLa cells and in human cervix carcinoma. Z Naturforsch 36c:552–561

  24. Pyerin W, Wolf CR, Kinzel V, Kübler D, Oesch F (1983) Phosphorylation of cytochrome-P-450-dependent monooxygenase components. Carcinogenesis 5:573–576

  25. Pyerin W, Taniguchi H, Stier A, Oesch F, Wolf CR (1984) Phosphorylation of rabbit liver cytochrome P-450 LM2 and its effect on monooxygenase activity. Biochem Biophys Res Commun 122:620–626

  26. Pyerin W, Marx M, Taniguchi H (1986) Phosphorylation of microsome-bound cytochrome P-450 LM2. Biochem Biophys Res Commun 134:461–468

  27. Roach PJ (1984) Protein kinases. Methods Enzymol 107:81–101

  28. Schenkman JB, Kupfer D (eds) (1982) Hepatic cytochrome P-450 monooxygenase system Pergamon Press, Oxford

  29. Sanghvi A, Grassi E, Warty V, Divenk W, Wight C, Lester R (1981) Reversible activation-inactivation of cholesterol 7α-hydroxylase possibly due to phosphorylation-dephosphorylation. Biochem Biophys Res Commun 103:886–892

  30. Taniguchi H, Imai Y, Sato R (1984) Role of the electron transfer system in microsomal drug monooxygenase reaction catalyzed by cytochrome P-450. Arch Biochem Biophys 232:585–596

  31. Taniguchi H, Pyerin W, Stier A (1985) Conversion of hepatic microsomal cytochrome P-450 to P-420 upon phosphorylation by cyclic AMP dependent protein kinase. Biochem Pharmacol 34:1835–1837

  32. Tarr GE, Black SD, Fujita VS, Coon MJ (1983) Complete amino acid sequence and predicted membrane topology of phenobarbital-induced cytochrome P-450 (isoenzyme 2) from rabbit liver microsomes. Proc Natl Acad Sci USA 80:6552–6556

  33. Ullrich V, Weber P (1972) The O-dealkylation of 7-ethoxycoumarin by liver microsomes; a direct fluorometric test. Hoppe Seylers Z Physiol Chem 353:1171–1177

  34. Wolf CR, Seilman S, Oesch F, Mayer RT, Burke MD (1986) Multiple forms of cytochrome P-450 related to forms induced marginally by phenobarbital. Biochem J (in press)

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Correspondence to W. Pyerin.

Additional information

Dedicated to Professor E. Hecker on the occasion of his 60th birthday

This work was supported in part by the Deutsche Forschungsgemeinschaft

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Pyerin, W., Horn, F. & Taniguchi, H. Posttranslational modifications of the cytochrome P-450 monooxygenase system. J Cancer Res Clin Oncol 113, 155–159 (1987). https://doi.org/10.1007/BF00391438

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Key words

  • Monooxygenase
  • Cytochrome P-450
  • NADPH-cytochrome P-450 reductase
  • Protein kinase
  • Phosphatase