Advertisement

Cytochrome P-450 — Its Function in the Oxidative Metabolism of Drugs

  • Ronald W. Estabrook
Part of the Handbook of Experimental Pharmacology / Handbuch der experimentellen Pharmakologie book series (HEP, volume 28 / 2)

Abstract

The oxidative transformation of a large variety of compounds of pharmacological interest is known to occur primarily in the liver. The participation in these reactions of an enzyme complex associated with the disrupted endoplasmic reticulum (microsomal fraction) of liver was established in the mid-1950’s by the group at the National Institutes of Health under the direction of B.B. Brodie (Brodie, 1955; Cooper and Brodie, 1955). Indeed, this laboratory has served as the major source of investigators and ideas for the work which has led to our present understanding of the multitude of parameters modifying drug metabolism. Biochemical studies on drug metabolism gained their initial impetus from the studies of R.T. Williams and his collaborators (1959), who identified many of the products formed in the body and characterized the major pathways of detoxification. Parallel to the studies by BRODIE and his group were a number of other investigations directly related to the biochemical mechanism of such oxidative reactions. Studies of the metabolic pathways for steroids (Samuels, 1961), the use of oxygen-18 to assess the role of molecular oxygen (Hayano et al., 1955; Mason, 1957; Hayaishi, 1962), the spectrophotometric study of microsomal pigments (Klingenberg, 1958), and the detailed investigation by pharmacologists of “drug tolerance” (Conney et al., 1956, 1960; Burns et al., 1955; Remmer, 1959), all came to the forefront at about the same time. Examination of each of these facets of the problem added to our present understanding of the mechanism of drug hydroxylation reactions, reactions that are now classified as mixed function oxidation (Mason, 1957) or monooxygenase (Hayaishi, 1962) type reactions.

Keywords

Liver Microsome Oxidative Metabolism Spectral Change Difference Spectrum Microsomal Fraction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Alvares, A.P., Schilling, G., Levin, W., Kuntzman, R.: Studies on the Induction of CO-Binding Pigments in Liver Microsomes by Phenobarbital and 3-Methylcholanthrene. Biochem. biophys. Res. Commun. 29, 521–526 (1967).PubMedCrossRefGoogle Scholar
  2. Brodie, B.B.: Detoxication of Drugs and Other Foreign Compounds by Liver Microsomes. Science 121, 603 (1955).PubMedCrossRefGoogle Scholar
  3. Burns, J.J., Rose, K., Goodwin, S., Reichenthol, J., Horning, E.C., Brodie, B.B.: Metabolic Fate of Phenylbutazone in Man. Amer. J. Pharm. 113, 481–489 (1955).Google Scholar
  4. Cammer, W., Schenkman, J.B., Estabrook, R.W.: EPR Measurements of Substrate Interaction with Cytochrome P-450. Biochem. biophys. Res. Commun. 23, 264–268 (1968).CrossRefGoogle Scholar
  5. Chance, B.: Techniques for the Assay of the Respiratory Enzymes. In: Methods in Enzymology, Vol IV, pp. 273–329. Ed. by S.P. Colowick, and N.O. Kaplan. New York: Academic Press 1957.Google Scholar
  6. Chance, B., Pappenheimer, A.M., Jr.: Kinetic and Spectrophotometric Studies of Cytochrome b5 in Midgut Homogenates of Cecropia. J. biol. Chem. 209, 931–944 (1954).PubMedGoogle Scholar
  7. Chance, B., Williams, G. R.: Kinetics of Cytochrome b5 in Rat Liver Microsomes. J. biol. Chem. 209, 945–951 (1954).PubMedGoogle Scholar
  8. Conney, A.H., Brown, R.R., Miller, J.A., Miller, E.C.: The Metabolism of Methylated Aminoazo Dyes. VI. Intracellular Distribution and Properties of the Demethylase System. Cancer Res. 17, 628–634 (1957).PubMedGoogle Scholar
  9. Conney, A.H., Davison, C., Gastel, R., Burns, J.J.: Adaptive Increases in Drug Metabolizing Enzymes Induced by Phenobarbital and other Drugs. J. Pharmacol. exp. Ther. 130, 1–8 (1960).PubMedGoogle Scholar
  10. Conney, A.H., Miller, E.C,, Miller, J.A.: The Metabolism of Methylated Aminoazo Dyes. V. Evidence for Induction of Enzyme Synthesis in the Rat by 3-Methylcholanthrene. Cancer Res. 16, 450–459 (1956).PubMedGoogle Scholar
  11. Cooper, D.Y., Estabrook, R.W., Rosenthal, O.: The Stoichiometry of C21 Hydroxylation of Steroids by Adrenocortical Microsomes. J. biol. Chem. 238, 1320–1323 (1962).Google Scholar
  12. Cooper, D.Y., Levine, S., Narashimhulu, S., Rosenthal, O., Estabrook, R.W.: Photochemical Action Spectrum of the Terminal Oxidase of Mixed Function Oxidase Systems. Science 147, 400–402 (1965a).PubMedCrossRefGoogle Scholar
  13. Cooper, D.Y., Narashimhulu, S., Rosenthal, O., Estabrook, R.W.: Spectral and Kinetic Studies of Microsomal Pigments. In: Oxidases and Related Redox Systems, pp. 838–860. Ed. by T.E. King, H.S. Mason and M. Morrison. New York: Wiley 1965b.Google Scholar
  14. Cooper, J.R., Brodie, B.B.: The Enzymatic Metabolism of Hexobarbital (Evipal). J. Pharmacol. exp. Ther. 114, 409–417 (1955).PubMedGoogle Scholar
  15. Dallner, G., Siekevttz, P., Palade, G.E.: Biogenesis ofEndoplasmicReticulumMembranes. II. Synthesis of Ceris Titertive Microsomal Enzymes in Developing Rat Hepatocytes. J. Cell Biol. 30, 97–117 (1966).PubMedCrossRefGoogle Scholar
  16. Estabrook, R.W., Cohen, B.: Organization of the Microsomal Electron Transport System. In: Microsomes and Drug Oxidation, pp. 95–105. Ed. by J. Gillette et al. New York: Academic Press 1969.Google Scholar
  17. Estabrook, R.W., Cooper, D.Y., Rosenthal, O.: The Light reversible Carbon Monoxide Inhibition of the Steroid C-21-Hydroxylase System of Adrenal Cortex. Biochem. Z. 338, 741–755 (1963).PubMedGoogle Scholar
  18. Estabrook, R.W., Hildebrandt, A., Remmer, H., Schenkman, J.B., Rosenthal, O., Cooper, D.Y.: The Role of Cytochrome P-450 in Microsomal Mixed Function Oxidation Reactions. In: The 19 Colloquium der Gesellschaft für Biologische Chemie, pp. 142–177. Ed. by B. Hess and H.J. Staudinger. Berlin-Heidelberg-New York: Springer 1969.Google Scholar
  19. Estabrook, R.W., Netter, K., Pawar, S., Hildebrandt, A., Leibman, K.: Steady State of Cytochrome P-450 of Liver Microsomes During Drug Hydroxylation Reactions. Fed. Proc. 29, 874 (1970).Google Scholar
  20. Garfinkel, D.: Studies on Pig Liver Microsomes I. Enzymic and Pigment Composition of Different Microsomal Fractions. Arch. Biochem. 77, 493–509 (1958).PubMedCrossRefGoogle Scholar
  21. Gigon, P.L., Gram, T.E., Gillette, J.R.: Studies on the Rate of Reduction of Hepatic Microsomal Cytochrome P-450 by Reduced Nicotinamide Adenine Dinucleotide Phosphate: Effect of Drug Substrates. Molec. Pharmacol. 5, 109–122 (1969).Google Scholar
  22. Hashimoto, Y., Yamano, T., Mason, H.S.: An Electron Spin Resonance Study of Microsomal Electron Transport. J. biol. Chem. 237, 3843–3844 (1962).PubMedGoogle Scholar
  23. Hayaishi, O.: Oxygenases. New York: Academic Press 1962.Google Scholar
  24. Hayano, M., Lindberg, M.D., Dorfman, R.I., Hancock, J.E.H., Von Doering, E.W.: On the Mechanisms of the C-11β-Hydroxylation of Steroids; with H2O2 and O2 18. Arch. Biochem. 59, 529–532 (1955).PubMedCrossRefGoogle Scholar
  25. Hildebrandt, A., Estabrook, R.W.: DPNH and Ionic Strength as Positive Effectors of Microsomal Mixed Function Oxidations. Fed. Proc. 29, 738 (1970a).Google Scholar
  26. Hildebrandt, A., Estabrook, R.W.: unpublished results (1970b).Google Scholar
  27. Hildebrandt, A., Remmer, H., Estabrook, R.W.: Cytochrome P-450 of Liver Microsomes — One Pigment or Many. Biochem. biophys. Res. Commun. 30, 607–612 (1969).CrossRefGoogle Scholar
  28. Imai, Y., Sato, R.: Substrate Interaction with Hydroxylase System in Liver Microsomes. Biochem. biophys. Res. Commun. 22, 620–626 (1966).PubMedCrossRefGoogle Scholar
  29. Katagiri, M., Ganguli, B.N., Gunsalus, I.C.: A Soluble Cytochrome P-450 Functional in Methylene Hydroxylation. J. biol. Chem. 243, 3543–3545 (1968).PubMedGoogle Scholar
  30. Keilin, D., Hartree, E.F.: Succinic Dehydrogenous-Cytochrome System of Cells. Proc. roy. Soc. B 129, 277–306 (1940).CrossRefGoogle Scholar
  31. Klingenberg, M.: Pigments of Rat Liver Microsomes. Arch. Biochem. 75, 379–386 (1958).CrossRefGoogle Scholar
  32. Leibman, K.C., Hildebrandt, A.G., Estabrook, R.W.: Spectrophotometric Studies of Interaction Between Various Substrates in Their Binding to Microsomal Cytochrome P-450. Biochem biophys. Res. Commun. 36, 789–794 (1969).PubMedCrossRefGoogle Scholar
  33. Levin, W., Kuntzman, R.: Biphasic Decrease of Radioactive Hemoprotein from Liver Microsomal CO-Binding Particles. Effect of 3-Methylcholanthrene. J. biol. Chem. 244, 3671–3684 (1969a).PubMedGoogle Scholar
  34. Levin, W., Kuntzman, R.: Biphasic Decrease of Radioactive Hemoprotein from Liver Microsomal CO-Binding Particles. Effect of Phenobarbital and Chlordane. Molec. Pharmacol. 5, 499–506 (1969b).Google Scholar
  35. Mason, H.S.: Mechanism of Oxygen Metabolism. In: Advances in Enzymology. Vol. XIX. Ed. by F.F. Nord. New York: Chider Science Publ., Inc. 1957.Google Scholar
  36. Mason, H.S., North, J.C., Vanneste, M.: Microsomal Mixed Function Oxidations, The Metabolism of Xenobiotics. Symposium on Electron Transport Systems in Microsomes. Fed. Proc. 24, 1172–1180 (1965a).PubMedGoogle Scholar
  37. Mason, H.S., Yamano, T., North, J.C., Hashmoto, Y., Sakagishi, P.: The Structure and Oxidase Function of Liver Microsomes. In: Oxidases and Related Redox Systems, pp. 879–899. Ed. by T.E. King, H.S. Mason and M. Morrison. New York: Wiley 1965b.Google Scholar
  38. Narasimhulu, S., Cooper, D.Y., Rosenthal, O.: Spectrophotometric Properties of a Trition Clarified Steroid 21-Hydroxylase System of Adrenocortical Microsomes. Life Sci. 4, 2101–2107 (1965).PubMedCrossRefGoogle Scholar
  39. Omura, T., Sato, R.: A New Cytochrome in Liver Microsomes. J. biol. Chem. 237, 1375 to 1381 (1962).PubMedGoogle Scholar
  40. Omura, T., Sato, R.: The Carbon Monoxide-Binding Pigment of Liver Microsomes. I. Evidence for Its Hemoprotein Nature. J. biol. Chem. 239, 2370–2378 (1964a).PubMedGoogle Scholar
  41. Omura, T., Sato, R.: The Carbon Monoxide-Binding Pigment of Liver Microsomes. II. Solubilization, Purification and Properties. J. biol. Chem. 239, 2379–2385 (1964b).PubMedGoogle Scholar
  42. Omura, T., Sato, R., Cooper, D.Y., Rosenthal, O., Estabrook, R.W.: Functions of Cytochrome P-450 of Microsomes. Symposium on Electron Transport System in Microsomes. Fed. Proc. 24, 1181–1189 (1965).PubMedGoogle Scholar
  43. Orrenius, S., Ernster, L.: Phenobarbital-induced Synthesis of the Oxidative Demethylating Enzymes of Rat Liver Microsomes. Biochem. biophys. Res. Commun. 16, 60–65 (1964).PubMedCrossRefGoogle Scholar
  44. Pappenheimer, A.M., Jr., Williams, C.M.: Cytochrome bs and the Dihydrocoenzyme Oxidase System in the Cecropia Silkworm. J. biol. Chem. 209, 915–929 (1954).PubMedGoogle Scholar
  45. Remmer, H.: Der beschleunigte Abbau von Pharmaka in den Lebermicrosomen unter dem Einfluß von Luminal. Naunyn-Schmiedeberg’s Arch. exp. Path. Parmak. 235, 279–290 (1959).Google Scholar
  46. Remmer, H., Schenkman, J.B., Estabrook, R.W., Sasame, H., Gillette, J., Narashimhulu, S., Cooper, D.Y., Rosenthal, O.: Drug Interaction with Hepatic Microsomal Cytochrome. Molec. Pharmacol. 2, 187–190 (1966).Google Scholar
  47. Ryan, K.G., Engel, L.: Hydroxylation of Steroids at Carbon 21. J. biol. Chem. 225, 103–114 (1957).PubMedGoogle Scholar
  48. Samuels, L.T.: Metabolism of Steroid Hormones. In: Metabolic Pathways, Vol. I, pp. 431 to 438. Ed. by D.M. Greenberg. New York: Academic Press 1961.Google Scholar
  49. Schenkman, J.B., Remmer., H., Estabrook, R.W.: Spectral Studies of Drug Interaction with Hepatic Microsomal Cytochrome. Molec. Pharmacol. 3, 113–123 (1967).Google Scholar
  50. Shoeman, D.W., Chaplin, M.D., Mannering, G.J.: Induction of Drug Metabolism. III. Further Evidence for the Formation of a New P-450 Hemoprotein After Treatment of Rats with 3-Methylcholanthrene. Molec. Pharmacol. 5, 412–419 (1969a).Google Scholar
  51. Shoeman, D.W., White, J.G., Mannering, G.J.: Cytochrome P-450: Tubular Aggregates from Hepatic Microsomes. Science 165, 1371–1372 (1969b).PubMedCrossRefGoogle Scholar
  52. Sladek, N.E., Mannering, G.J.: Evidence for a New P-450 Hemoprotein in Hepatic Microsomes from Methylcholanthrene Treated Rats. Biochem. biophys. Res. Commun. 24, 668–674 (1966).CrossRefGoogle Scholar
  53. Strittmatter, C.F., Ball, E.G.: A Hemochromogen Component of Liver Microsomes. Proc. nat. Acad. Sci. (Wash.) 38, 19–37 (1952).CrossRefGoogle Scholar
  54. Ullrich, V., Cohen, B., Cooper, D.Y., Estabrook, R.W.: Reactions of Hemoprotein P-450. In: Structure and Function of Cytochromes, pp. 649–655. Ed. by K. Okunuki, M.D. Kamen and I. Sekuzu. University of Tokyo Press 1968.Google Scholar
  55. Warburg, O.: Heavy Metal Prosthetic Groups and Enzyme Action. London and New York: Oxford University Press (Clarendon) 1949.Google Scholar
  56. Waterman, M., Mason, H.S.: The Redox Potential of Liver Cytochrome P-450. Biochem. biophys. Res. Commun. 39, 450–454 (1970).PubMedCrossRefGoogle Scholar
  57. Williams, R.T.: Detoxication Mechanisms, 2nd Ed. London: Chapman and Hall 1959.Google Scholar

Copyright information

© Springer-Verlag Berlin · Heidelberg 1971

Authors and Affiliations

  • Ronald W. Estabrook

There are no affiliations available

Personalised recommendations