Intracellular transport and localization of microsomal cytochrome P450



The cytochrome P450 (P450) enzymes are mainly localized to the endoplasmic reticulum (ER), where they function within catalytic complexes metabolizing xenobiotics and some endogenous substrates. However, certain members of families 1–3 were also found in other subcellular compartments, such as mitochondria, plasma membrane, and lysosomes. The physiological function of these enzymes in non-ER locations is not known, although plasma-membrane-associated P450s have been described to be catalytically active and to participate in immune-mediated reactions with autoantibody formation that can trigger drug-induced hepatitis. Several retention/retrieval mechanisms are active in the ER retention of the P450s and inverse integration of the translated P450 into the ER membrane appears to be responsible for transport to the plasma membrane. Furthermore, hydrophilic motifs in the NH2-terminal part have been suggested to be important for mitochondrial import. Phosphorylation of P450s has been described to be important for increased rate of degradation as well as for targeting into mitochondria. It was also suggested that the mitochondria-targeted P450s from families 1–3 could be active in drug metabolism using an alternative electron transport chain. In this review we present an update of the field emphasizing studies concerning localization, posttranslational modification, such as phosphorylation, and intracellular transport of microsomal P450s.


Microsomal P450s Mitochondria Phosphorylation Plasma membrane Protein targeting Degradation 


  1. 1.
    Beaune P, Pessayre D, Dansette P, Mansuy D, Manns M (1994) Adv Pharmacol 30:199–245CrossRefGoogle Scholar
  2. 2.
    Lecoeur S, Andre C, Beaune PH (1996) Mol Pharmacol 50:326–333Google Scholar
  3. 3.
    Eliasson E, Kenna JG (1996) Mol Pharmacol 50:573–582Google Scholar
  4. 4.
    Clot P, Albano E, Eliasson E, Tabone M, Arico S, Israel Y, Moncada C, Ingelman-Sundberg M (1996) Gastroenterology 111:206–216CrossRefGoogle Scholar
  5. 5.
    Bhagwat SV, Boyd MR, Ravindranath V (1995) Arch Biochem Biophys 320:73–83CrossRefGoogle Scholar
  6. 6.
    Anandatheerthavarada HK, Addya S, Dwivedi RS, Biswas G, Mullick J, Avadhani NG (1997) Arch Biochem Biophys 339:136–150CrossRefGoogle Scholar
  7. 7.
    Bhagwat SV, Mullick J, Raza H, Avadhani NG (1999) Toxicol Appl Pharmacol 156:231–240CrossRefGoogle Scholar
  8. 8.
    Neve EPA, Ingelman-Sundberg M (1999) FEBS Lett 460:309–314CrossRefGoogle Scholar
  9. 9.
    Sakaguchi M, Mihara K, Sato R (1984) Proc Natl Acad Sci USA 81:3361–3364CrossRefGoogle Scholar
  10. 10.
    Sakaguchi M, Tomiyoshi R, Kuroiwa T, Mihara K, Omura T (1992) Proc Natl Acad Sci USA 89:16–19CrossRefGoogle Scholar
  11. 11.
    Monier S, Van Luc P, Kreibich G, Sabatini DD, Adesnik M (1988) J Cell Biol 107:457–470CrossRefGoogle Scholar
  12. 12.
    Bar-Nun S, Kreibich G, Adesnik M, Alterman L, Negishi M, Sabatini DD (1980) Proc Natl Acad Sci USA 77:965–969CrossRefGoogle Scholar
  13. 13.
    Sato T, Sakaguchi M, Mihara K, Omura T (1990) EMBO J 9:2391–2397Google Scholar
  14. 14.
    Black SD (1992) FASEB J 6:680–685Google Scholar
  15. 15.
    Szczesna-Skorupa E, Kemper B (1989) J Cell Biol 108:1237–1243CrossRefGoogle Scholar
  16. 16.
    Kusano K, Sakaguchi M, Kagawa N, Waterman MR, Omura T (2001) J Biochem 129:259–269Google Scholar
  17. 17.
    Ivessa NE, De Lemos-Chiarandini C, Tsao YS, Takatsuki A, Adesnik M, Sabatini DD, Kreibich G (1992) J Cell Biol 117:949–958CrossRefGoogle Scholar
  18. 18.
    Pelham HR (1990) Trends Biochem Sci 15:483–486CrossRefGoogle Scholar
  19. 19.
    Cosson P, Letourneur F (1994) Science 263:1629–1631CrossRefGoogle Scholar
  20. 20.
    Martinez-Menarguez JA, Geuze HJ, Slot JW, Klumperman J (1999) Cell 98:81–90CrossRefGoogle Scholar
  21. 21.
    Barlowe C (2003) Trends Cell Biol 13:295–300CrossRefGoogle Scholar
  22. 22.
    Nishimura N, Balch WE (1997) Science 277:556–558CrossRefGoogle Scholar
  23. 23.
    Ma D, Zerangue N, Lin YF, Collins A, Yu M, Jan YN, Jan LY (2001) Science 291:316–319CrossRefGoogle Scholar
  24. 24.
    Kappeler F, Klopfenstein DR, Foguet M, Paccaud JP, Hauri HP (1997) J Biol Chem 272:31801–31808CrossRefGoogle Scholar
  25. 25.
    Fiedler K, Veit M, Stamnes MA, Rothman JE (1996) Science 273:1396–1399CrossRefGoogle Scholar
  26. 26.
    Farquhar MG, Palade GE (1998) Trends Cell Biol 8:2–10CrossRefGoogle Scholar
  27. 27.
    Ahn K, Szczesna-Skorupa E, Kemper B (1993) J Biol Chem 268:18726–18733Google Scholar
  28. 28.
    Murakami K, Mihara K, Omura T (1994) J Biochem 116:164–175Google Scholar
  29. 29.
    Szczesna-Skorupa E, Ahn K, Chen CD, Doray B, Kemper B (1995) J Biol Chem 270:24327–24333CrossRefGoogle Scholar
  30. 30.
    Szczesna-Skorupa E, Chen CD, Kemper B (2000) Arch Biochem Biophys 374:128–136CrossRefGoogle Scholar
  31. 31.
    Szczesna-Skorupa E, Kemper B (2000) J Biol Chem 275:19409–19415CrossRefGoogle Scholar
  32. 32.
    Szczesna-Skorupa E, Kemper B (2006) J Biol Chem 281:4142–4148CrossRefGoogle Scholar
  33. 33.
    Ingelman-Sundberg M (1986) In: Ortiz de Montellano PR (ed) Cytochrome P450 structure, mechanisms and biochemistry. Plenum, New YorkGoogle Scholar
  34. 34.
    Myasoedova KN, Berndt P (1990) FEBS Lett 275:235–238CrossRefGoogle Scholar
  35. 35.
    Szczesna-Skorupa E, Chen CD, Rogers S, Kemper B (1998) Proc Natl Acad Sci USA 95:14793–14798CrossRefGoogle Scholar
  36. 36.
    Szczesna-Skorupa E, Mallah B, Kemper B (2003) J Biol Chem 278:31269–31276CrossRefGoogle Scholar
  37. 37.
    Neve EPA, Eliasson E, Pronzato MA, Albano E, Marinari U, Ingelman-Sundberg M (1996) Arch Biochem Biophys 333:459–465CrossRefGoogle Scholar
  38. 38.
    Cotman M, Jezek D, Fon Tacer K, Frangez R, Rozman D (2004) Endocrinology 145:1419–1426CrossRefGoogle Scholar
  39. 39.
    Homma K, Yoshida Y, Nakano A (2000) J Biochem 127:747–754Google Scholar
  40. 40.
    Ronis MJ, Johansson I, Hultenby K, Lagercrantz J, Glaumann H, Ingelman-Sundberg M (1991) Eur J Biochem 198:383–389CrossRefGoogle Scholar
  41. 41.
    Loeper J, Descatoire V, Maurice M, Beaune P, Feldmann G, Larrey D, Pessayre D (1990) Hepatology 11:850–858CrossRefGoogle Scholar
  42. 42.
    Loeper J, Descatoire V, Maurice M, Beaune P, Belghiti J, Houssin D, Ballet F, Feldmann G, Guengerich FP, Pessayre D (1993) Gastroenterology 104:203–216Google Scholar
  43. 43.
    Neve EPA, Ingelman-Sundberg M (2000) J Biol Chem 275:17130–17135CrossRefGoogle Scholar
  44. 44.
    Wu D, Cederbaum AI (1992) Hepatology 15:515–524CrossRefGoogle Scholar
  45. 45.
    Robin MA, Maratrat M, Loeper J, Durand-Schneider AM, Tinel M, Ballet F, Beaune P, Feldmann G, Pessayre D (1995) Gastroenterology 108:1110–1123CrossRefGoogle Scholar
  46. 46.
    Robin MA, Descatoire V, Le Roy M, Berson A, Lebreton FP, Maratrat M, Ballet F, Loeper J, Pessayre D (2000) J Pharmacol Exp Ther 294:1063–1069Google Scholar
  47. 47.
    Robin MA, Maratrat M, Le Roy M, Le Breton FP, Bonierbale E, Dansette P, Ballet F, Mansuy D, Pessayre D (1996) J Clin Invest 98:1471–1480CrossRefGoogle Scholar
  48. 48.
    De Lemos-Chiarandini C, Frey AB, Sabatini DD, Kreibich G (1987) J Cell Biol 104:209–219CrossRefGoogle Scholar
  49. 49.
    Trautwein C, Gerken G, Lohr H, Meyer zum Buschenfelde KH, Manns M (1993) Z Gastroenterol 31:225–230Google Scholar
  50. 50.
    Loeper J, Louerat-Oriou B, Duport C, Pompon D (1998) Mol Pharmacol 54:8–13Google Scholar
  51. 51.
    van der Laan M, Rissler M, Rehling P (2006) FEMS Yeast Res 6:849–861CrossRefGoogle Scholar
  52. 52.
    Bolender N, Sickmann A, Wagner R, Meisinger C, Pfanner N (2008) EMBO Rep 9:42–49CrossRefGoogle Scholar
  53. 53.
    Abe Y, Shodai T, Muto T, Mihara K, Torii H, Nishikawa S, Endo T, Kohda D (2000) Cell 100:551–560CrossRefGoogle Scholar
  54. 54.
    Neupert W, Herrmann JM (2007) Annu Rev Biochem 76:723–749CrossRefGoogle Scholar
  55. 55.
    Omura T (2006) Chem Biol Interact 163:86–93CrossRefGoogle Scholar
  56. 56.
    Niranjan BG, Avadhani NG (1980) J Biol Chem 255:6575–6578Google Scholar
  57. 57.
    Das M, Seth PK, Dixit R, Mukhtar H (1982) Arch Biochem Biophys 217:205–215CrossRefGoogle Scholar
  58. 58.
    Anandatheerthavarada HK, Vijayasarathy C, Bhagwat SV, Biswas G, Mullick J, Avadhani NG (1999) J Biol Chem 274:6617–6625CrossRefGoogle Scholar
  59. 59.
    Robin MA, Anandatheerthavarada HK, Fang JK, Cudic M, Otvos L, Avadhani NG (2001) J Biol Chem 276:24680–24689CrossRefGoogle Scholar
  60. 60.
    Anandatheerthavarada HK, Biswas G, Mullick J, Sepuri NB, Otvos L, Pain D, Avadhani NG (1999) EMBO J 18:5494–5504CrossRefGoogle Scholar
  61. 61.
    Addya S, Anandatheerthavarada HK, Biswas G, Bhagwat SV, Mullick J, Avadhani NG (1997) J Cell Biol 139:589–599CrossRefGoogle Scholar
  62. 62.
    Robin MA, Anandatheerthavarada HK, Biswas G, Sepuri NB, Gordon DM, Pain D, Avadhani NG (2002) J Biol Chem 277:40583–40593CrossRefGoogle Scholar
  63. 63.
    Mijaljica D, Prescott M, Devenish RJ (2006) Traffic 7:1590–1595CrossRefGoogle Scholar
  64. 64.
    Glickman MH, Ciechanover A (2002) Physiol Rev 82:373–428Google Scholar
  65. 65.
    Correia MA (2003) Drug Metab Rev 35:107–143CrossRefGoogle Scholar
  66. 66.
    Murray BP, Zgoda VG, Correia MA (2002) Mol Pharmacol 61:1146–1153CrossRefGoogle Scholar
  67. 67.
    Liao M, Zgoda VG, Murray BP, Correia MA (2005) Mol Pharmacol 67:1460–1469CrossRefGoogle Scholar
  68. 68.
    Zhukov A, Ingelman-Sundberg M (1999) Biochem J 340:453–458CrossRefGoogle Scholar
  69. 69.
    Roberts BJ, Song BJ, Soh Y, Park SS, Shoaf SE (1995) J Biol Chem 270:29632–29635CrossRefGoogle Scholar
  70. 70.
    Korsmeyer KK, Davoll S, Figueiredo-Pereira ME, Correia MA (1999) Arch Biochem Biophys 365:31–44CrossRefGoogle Scholar
  71. 71.
    Correia MA, Davoll SH, Wrighton SA, Thomas PE (1992) Arch Biochem Biophys 297:228–238CrossRefGoogle Scholar
  72. 72.
    Tierney DJ, Haas AL, Koop DR (1992) Arch Biochem Biophys 293:9–16CrossRefGoogle Scholar
  73. 73.
    Eliasson E, Johansson I, Ingelman-Sundberg M (1990) Proc Natl Acad Sci USA 87:3225–3229CrossRefGoogle Scholar
  74. 74.
    Eliasson E, Mkrtchian S, Halpert JR, Ingelman-Sundberg M (1994) J Biol Chem 269:18378–18383Google Scholar
  75. 75.
    Zhukov A, Ingelman-Sundberg M (1997) Eur J Biochem 247:37–43CrossRefGoogle Scholar
  76. 76.
    Iscan M, Reuhl K, Weiss B, Maines MD (1990) Biochem Biophys Res Commun 169:858–863CrossRefGoogle Scholar
  77. 77.
    Genter MB, Clay CD, Dalton TP, Dong H, Nebert DW, Shertzer HG (2006) Biochem Biophys Res Commun 342:1375–1381CrossRefGoogle Scholar
  78. 78.
    Neve EPA, Ingelman-Sundberg M (2001) J Biol Chem 276:11317–11322CrossRefGoogle Scholar
  79. 79.
    Pahan K, Smith BT, Singh AK, Singh I (1997) Free Radic Biol Med 23:963–971CrossRefGoogle Scholar
  80. 80.
    Koch JA, Waxman DJ (1989) Biochemistry 28:3145–3152CrossRefGoogle Scholar
  81. 81.
    Pyerin W, Taniguchi H, Stier A, Oesch F, Wolf CR (1984) Biochem Biophys Res Commun 122:620–626CrossRefGoogle Scholar
  82. 82.
    Pyerin W, Marx M, Taniguchi H (1986) Biochem Biophys Res Commun 134:461–468CrossRefGoogle Scholar
  83. 83.
    Johansson I, Eliasson E, Ingelman-Sundberg M (1991) Biochem Biophys Res Commun 174:37–42CrossRefGoogle Scholar
  84. 84.
    Eliasson E, Mkrtchian S, Ingelman-Sundberg M (1992) J Biol Chem 267:15765–15769Google Scholar
  85. 85.
    Menez JF, Machu TK, Song BJ, Browning MD, Deitrich RA (1993) Alcohol Alcohol 28:445–451Google Scholar
  86. 86.
    Oesch-Bartlomowicz B, Padma PR, Becker R, Richter B, Hengstler JG, Freeman JE, Wolf CR, Oesch F (1998) Exp Cell Res 242:294–302CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Etienne P. A. Neve
    • 1
  • Magnus Ingelman-Sundberg
    • 1
  1. 1.Section of Pharmacogenetics, Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden

Personalised recommendations