Skip to main content

Multiplicity and functional diversity of rat hepatic microsomal cytochrome P450 isozymes

  • Chapter
IUPHAR 9th International Congress of Pharmacology London 1984
  • 107 Accesses

Abstract

Three potential fates await lipophilic foreign chemicals that enter a living organism: the compounds remain unchanged, undergo spontaneous breakdown, or enzymatic metabolism. The biotransformation products are, in general, more water soluble and are more easily eliminated from the organism than the parent compounds. Hence, both the duration and intensity of action of many biologically active xenobiotics, including drugs, are determined largely by their rate of conversion to more polar products. Although the biotransformation of xenobiotics occurs in many tissues and organs of higher animals, the highest metabolic activity resides in the liver. The foundations for modern research in xenobiotic metabolism were established through the pioneering efforts of several investigators (Mueller & Miller, 1953; Axelrod, 1955; Brodie et al., 1955; Williams, 1959) during the 1950s.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • AXELROD, J. (1955). The enzymatic deamination of amphetamine. J. biol. Chem., 214, 753–763.

    PubMed  CAS  Google Scholar 

  • BRODIE, B.B., AXELROD, J., COOPER, J.R., GAUDETTE, L., LA DU, B.N., MITOMA, C. & UDENFRIEND, S. (1955). Detoxification of drugs and other foreign compounds by liver microsomes. Science, 121, 603–604.

    Article  PubMed  CAS  Google Scholar 

  • CONNEY, A.H. (1967). Pharmacological implications of microsomal enzyme induction. Pharmac. Rev., 19, 317–366.

    CAS  Google Scholar 

  • COOPER, D.Y., LEVINE, S., NARASIMHULU, S., ROSENTHAL, O. & ESTABROOK, R.W. (1965). Photochemical action spectrum of the terminal oxidase of mixed function oxidase systems. Science, 147, 400–402.

    Article  PubMed  CAS  Google Scholar 

  • DIETER, H.H. & JOHNSON, E.F. (1982). Functional and structural polymorphism of rabbit microsomal cytochrome P-450 form 3b. J. biol. Chem., 257, 9315–9323.

    PubMed  CAS  Google Scholar 

  • DIGNAM, J.D. & STROBEL, H.W. (1975). Preparation of homogeneous NADPH-cytochrome P-450 reductase from rat liver. Biochem. biophys. Res. Commun., 63, 845–852.

    Google Scholar 

  • FUJII-KURIYAMA, Y., MIZUKAMI, Y., KAWAJIRI, K., SOGAWA, K. & MURAMATSU, M. (1982). Primary structure of a cytochrome P-450: Coding nucleotide sequence of phenobarbital-inducible cytochrome P-450 cDNA from rat liver. Proc. natn. Acad. Sci. U.S.A., 79, 2793–2797.

    Google Scholar 

  • GUENGERICH, F.P., DANNAN, G.A., WRIGHT, S.T., MARTIN, M.V. & KAMINSKY, L.S. (1982). Purification and characterization of liver microsomal cytochromes P450; Electrophoretic, spectral, catalytic and immunological properties and inducibility of eight isozymes isolated from rats treated with phenobarbital or β-naphthoflavone. Biochemistry, 21, 6019–6030.

    Google Scholar 

  • GUSTAFSSON, J-A. & INGELMAN-SUNDBERG, M. (1974). Regulation and properties of a sex-specific hydroxylase system in female rat liver microsomes active on steroid sulfates. J. biol. Chem., 249, 1940–1945.

    Google Scholar 

  • HANIU, M., RYAN, D.E., LEVIN, W. & SHWELY, J.E. (1984). Structures of cysteine-containing peptides in isosafrole-inducible rat hepatic microsomal cytochrome P450: Sequence homology with 3-methylcholanthrene-induced cytochrome P450c. Proc. natn. Acad. Sci. U.S.A. (in press).

    Google Scholar 

  • HASHIMOTO, C. & IMAI, Y. (1976). Purification of a substrate complex of cytochrome P-450 from liver microsomes of 3-methylcholanthrene-treated rabbits. Biochem. biophys. Res. Commun., 68, 821–827.

    Google Scholar 

  • HAUGEN, D.A. & COON, M.J. (1976). Properties of electrophoretically homogeneous phenobarbital-inducible and β-naphthoflavone-inducible forms of liver microsomal cytochrome P450. J. biol. Chem., 251, 7929–7939.

    Google Scholar 

  • IMAI, Y. & SATO, R. (1974). A gel-electrophoretically homogeneous preparation of cytochrome P-450 from liver microsomes of phenobarbital-pretreated rabbits. Biochem. biophys. Res. Commun., 60, 8–14.

    Google Scholar 

  • JERINA, D.M., MICHAUD, D.P., FELDMANN, R.J., ARMSTRONG, R.N., VYAS, K.P., THAKKER, D.R. & 4 OTHERS (1982). Stereochemical modeling of the catalytic site of cytochrome P450c. In Microsomes, Drug Oxidations and Drug Toxiciry. Sato, R. & Kato, R. (eds) pp.195–201, New York: Wiley-Interscience.

    Google Scholar 

  • KUNZE, K.L., MANGOLD, B.L.K., WHEELER, C., BEILAN, H.S. & ORTIZ DE MONTELLANO, P.R. (1983). The cytochrome P-450 active site. Regiospecificity of prosthetic heme alkylation by olefins and acetylenes. J. biol. Chem., 258, 4202–4207.

    Google Scholar 

  • LAEMMLI, U.K. (1970). Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, 227, 680–685.

    Article  PubMed  CAS  Google Scholar 

  • MILLER, E.C. & MILLER, J.A. (1981). Searches for ultimate chemical carcinogens and their reactions with cellular macromolecules. Cancer, 47, 2327–2345.

    Google Scholar 

  • MUELLER, G.C. & MILLER, J.A. (1953). The metabolism of methylated aminoazo dyes. II. Oxidative demethylation by rat liver homogenates. J. biol. Chem., 202, 579–587.

    Google Scholar 

  • RYAN, D.E., IIDA, S., WOOD, A.W., THOMAS, P.E., LIEBER, C.S. & LEVIN, W. (1984). Characterization of three highly purified cytochromes P450 from hepatic microsomes of either untreated or ethanol-treated male rats. J. biol. Chem., 259, 1239–1250.

    Google Scholar 

  • RYAN, D.E., LU, A.Y.H., KAWALEK, J., WEST, S.B. & LEVIN, W. (1975). Highly purified cytochrome P-448 and P-450 from rat liver microsomes. Biochem. biophys. Res. Commun., 64, 1134–1141.

    Google Scholar 

  • RYAN, D.E., THOMAS, P.E., KORZENIOWSKI, D. & LEVIN, W. (1979). Separation and characterization of highly purified forms of liver microsomal cytochrome P-450 from rats pretreated with polychlorinated biphenyls, phenobarbital and 3-methylcholanthrene. J. biol. Chem., 254, 1365–1374.

    Google Scholar 

  • RYAN, D.E., THOMAS, P.E. & LEVIN, W. (1980). Hepatic microsomal cytochrome P450 from rats treated with isosafrole: Purification and characterization of four enzymic forms. J. biol. Chem., 255, 7941–7955.

    Google Scholar 

  • RYAN, D.E., THOMAS, P.E. & LEVIN, W. (1982a). Purification and characterization of a minor form of hepatic microsomal cytochrome P450 from rats treated with polychlorinated biphenyls. Archs Biochem. Biophys., 216, 272–288.

    Google Scholar 

  • RYAN, D.E., THOMAS, P.E., REIK, L.M. & LEVIN, W. (1982b). Purification, characterization and regulation of five rat hepatic microsomal cytochrome P450 isozymes. Xenobiotica, 12, 727–744.

    Google Scholar 

  • SHIVELY, J.E., HANIU, M., RYAN, D.E. & LEVIN, W. (1984). NH2-terminal sequences of four new rat hepatic microsomal cytochromes P450 and structure of the cysteine-containing peptides of the isosafrole-inducible rat hepatic microsomal cytochrome P450. Fedn Proc., 43, 2035.

    Google Scholar 

  • THOMAS, P.E., LU, A.Y.H., RYAN, D., WEST, S.B., KAWALEK, J. & LEVIN, W. (1976). Immunochemical evidence for six forms of rat liver cytochrome P450 using antibodies against purified rat liver cytochromes P450 and P448. Mol. Pharmac., 12, 746–758.

    Google Scholar 

  • THOMAS, P.E., REIK, L.M., RYAN, D.E. & LEVIN, W. (1981). Regulation of three forms of cytochrome P450 and epoxide hydrolase in rat liver microsomes. Effects of age, sex and induction. J. biol. Chem., 256, 1044–1052.

    Google Scholar 

  • THOMAS, P.E., REIK, L.M., RYAN, D.E. & LEVIN, W. (1983). Induction of two immuno-chemically related rat liver cytochrome P450 isozymes, cytochromes P450c and P450d, by structurally diverse xenobiotics. J. biol. Chem., 258, 4590–4598.

    Google Scholar 

  • THOMAS, P.E., REIK, L.M., RYAN, D.E. & LEVIN, W. (1984). Characterization of nine monoclonal antibodies against rat hepatic cytochrome P450c. Delineation of at least five spatially distinct epitopes. J. biol. Chem., 259, 3890–3899.

    Google Scholar 

  • VLASUK, G.P., GHRAYEB, J., RYAN, D.E., REIK, L., THOMAS, P.E., LEVIN, W. & WALZ, F.G. (1982). Multiplicity, strain differences and topology of phenobarbital-induced cytochromes P450 in rat liver microsomes. Biochemistry, 21, 789–798.

    Google Scholar 

  • WILLIAMS, R.T. (1959). Detoxication Mechanisms, 2nd edition, pp. 1–796, New York: John Wiley & Sons, Inc.

    Google Scholar 

  • WOLF, C.R., STATHAM, C.N., McMENAMIN, M.G., BEND, J.R., BOYD, M.R. & PHILPOT, R.M. (1982). The relationship between catalytic activities of rabbit pulmonary cytochrome P450 isozymes and the lung-specific toxicity of the furan derivative, 4-ipomenol. Mol. Pharmac., 22, 738–744.

    CAS  Google Scholar 

  • WOOD, A.W., RYAN, D.E., THOMAS, P.E. & LEVIN, W. (1983). Regio- and stereoselective metabolism of two C19 steroids by five highly purified and reconstituted rat hepatic cytochrome P450 isozymes. J. biol. Chem., 258, 8839–8847.

    PubMed  CAS  Google Scholar 

  • YASUKOCHI, Y. & MASTERS, B.S.S. (1976). Some properties of a detergent-solubilized NADPH-cytochrome c (cytochrome P450) reductase purified by biospecific affinity chromatography. J. biol. Chem., 251, 5337–5344.

    PubMed  CAS  Google Scholar 

  • YUAN, P-M., RYAN, D.E., LEVIN, W. & SHIVELY, J.E. (1983). Identification and localization of amino acid substitutions between two phenobarbital-inducible rat hepatic microsomal cytochromes P450 by micro sequence analyses. Proc. natn. Acad. Sci. U.S.A. 80, 1169–1173.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

William Paton James Mitchell Paul Turner Cheryl Padgham Eileen Ashcroft

Copyright information

© 1984 Macmillan Publishers Limited

About this chapter

Cite this chapter

Levin, W., Thomas, P.E., Reik, L.M., Wood, A.W., Ryan, D.E. (1984). Multiplicity and functional diversity of rat hepatic microsomal cytochrome P450 isozymes. In: Paton, W., Mitchell, J., Turner, P., Padgham, C., Ashcroft, E. (eds) IUPHAR 9th International Congress of Pharmacology London 1984. Palgrave Macmillan, London. https://doi.org/10.1007/978-1-349-17615-1_30

Download citation

Publish with us

Policies and ethics