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Oncology General Principles Continued


Mixed function oxidase System (Cytochrome 450 System)--Phase I Reactions44 
  • Microsomes have been used to study mixed function oxidases

    • Drug metabolizing enzymes are located in lipophilic, hepatic endoplasmic reticulum membranes.  Smooth endoplasmic reticulum contains those enzymes responsible for drug metabolism.

  • The reaction:

    • one molecule oxygen is consumed per substrate molecule

    • one oxygen atom -- appears in the product; the other in the form of water

    • Oxidation-Reduction Process:

Cytochrome p450 cycle (diagram by  Matthew Segall, 1997)

  1. "The binding of a substrate to a P450 causes a lowering of the redox potential by approximately 100mV, which makes the transfer of an electron favourable from its redox partner, NADH or NADPH.

  2. The first reduction -The next stage in the cycle is the reduction of the Fe3+ ion by an electron transfered from NAD(P)H via an electron transfer chain.

  3. Oxygen binding An O2 molecule binds rapidly to the ion Fe2+ forming Fe2+-O2

  4. Second reduction A second reduction is required by the stoichiometry of the reaction. This has been determined to be the rate-determining step of the reaction

  5. O2 cleavage: The O2 reacts with two protons from the surrounding solvent, breaking the O-O bond, forming water and leaving an Fe-O3+ complex.

  6. Product formation The Fe-ligated O atom is transferred to the substrate forming an hydroxylated form of the substrate.

  7. Product release The product is released from the active site of the enzyme which returns to its initial state."--Matthew Segall, 1997

  • "The active site of substrate-free cytochrome p450: Note the water molecule (which can be seen as a single oxygen atom) that forms the sixth axial ligand of the haem iron. Oxygen atoms are shown in red, nitrogen in light blue, sulphur in yellow and iron in dark blue. Carbon atoms are shown in grey as bonds only and hydrogens have been omitted from this figure for clarity."

  • "The active site of camphor-bound cytochrome p450cam , an example of a substrate-bound system. Note the absence of the water molecule which formed the sixth axial ligand of the haem iron in the substrate-free enzyme."

  • " A representation of with bound camphor. The enlarged active site region shows the camphor substrate, haem moiety and cysteine residue which forms the distal haem ligand. In the representation of the full enzyme the protein backbone is shown in green, the haem moiety in blue and the substrate is coloured according to atomic species. Oxygen atoms are shown in red, carbon in grey, nitrogen in light blue, sulphur in yellow and iron in dark blue."-diagrams and text  by  Matthew Segall, 1997

  • Cytochrome P450 Enzyme Induction:

    • Following repeated administration, some drugs increase the amount of P450 enzyme usually by:

      • increase enzyme synthesis rate (induction)

      • reduced enzyme degradation rate

  • Cytochrome P450 enzyme inhibition:

    • Certain drugs, by binding to the cytochrome component, act to competitively inhibit metabolism. Examples:

      •  Cimetidine (Tagamet) (anti-ulcer --H2 receptor blocker) and Ketoconazole (Nizoral) (antifungal) bind to the heme iron a cytochrome P450, reducing the metabolism of:

        • testosterone

        • other coadministered drugs

        • Mechanism of Action: competitive inhibition

    •  Catalytic inactivation of cytochrome P450.

      •  Macrolide antibiotics (troleandomycin, erythromycin estolate (Ilosone)), metabolized by a cytochrome P450:

        • metabolites complex with cytochrome heme-iron: producing a complex that is catalytically inactive.

      •  Chloramphenicol (Chloromycetin): metabolized by cytochrome P450 to an alkylating metabolite that inactivates cytochrome P450

      •  Other inactivators: Mechanism of Action: -- targeting the heme moiety:

        • steroids:

          • ethinyl estradiol (Estinyl)

          • norethindrone (Aygestin)

          • spironolactone (Aldactone)

        • others:

          • propylthiouracil

          • ethchlorvynol (Placidyl)

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  1. Rugo H.S., "Cancer" in 2008 Current Medical Diagnosis & Treatment (McPhee, S.J. and Papadakis, M.A., eds; Tierney, L.M. Jr, senior editor) McGraw-Hill Lange, 2008, New York 47th edition, pp. 1387-1390.

  2. SEER (Surveillance Epidemiology and End Results), 2008

  3. Information from SEER Cancer Statistics Review and reference 1.

  4. SEER graphs (Surveillance Epidemiology and End Results)

  5. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ Cancer Statistics 2007, CA Cancer J. Clin 2007; 43-66. (current as of May 17, 2008); online version ( ).

  6. Li FP, Peters ES "Cancer Epidemiology and Prevention" in ACP Medicine 2004-2005 Edition (Antman K, Atkinson JP, Cassel CK, Feldman M, Gibbons RJ, Haynes B, Henrich JB, Holtzman MJ, Lebwohl MG, Levinson W, Loriaux DL, Ruddy S, Wolinsky, JS, eds; Federman DD, Founding Editior, Dale DC, Editor-in-Chief) WebMD, 2004, pp 2313-2321.

  7. Doll, R Epidemiological Evidence of the Effects of Behaviour and the Environment on the Risk of Human Cancer. Recent Results Cancer Res, 1998; 154: 3-21.

  8. Boice JD Jr, Lubin JH Occupational and environmental radiation and cancer. Cancer Causes and Control, 1997, 8, pp. 309-322.

  9. Dienstag JL "Acute Viral Hepatitis" in Harrison's Principles of Internal Medicine, 17th edition, (Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL and Loscalzo J, eds) McGraw-Hill Medical, New York, 2008, pp 1932-1945.

  10. Carr BI "Tumors of the Liver and Biliary Tree"  in Harrison's Principles of Internal Medicine, 17th edition, (Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL and Loscalzo J, eds) McGraw-Hill Medical, New York, 2008, pp 581-582.

  11. Eng C "Anal Cancer" in MD Anderson Manual of Medical Oncology, (Kantarjian HM, Wolff RA, Koller CA, eds) McGraw-Hill Medical, New York, 2006, p.432.

  12. Butel JS "Herpesviruses" in Jawetz, Melnick & Adelberg's Medical Microbiology, 24th editions, Lange Microbiology, (Brooks GF, Carroll, KC, Butel JS, Morse, SA, eds), Chapter 33, 2007, on-line edition.

  13. Hunt, R. Virology-Chapter 7, Part 2: "The History of Disease:  Human Immunodeficiency Virus and AIDS". Microbiology and Immunology On-Line, University of South Carolina, School of Medicine (,

  14. Casper, C. "Human Herpesvirus-8, Kaposi's sarcoma and AIDS-Associated Neoplasm", HIV InSite (, 2008.

  15. Escalon MP, Hagenmeister, FB  "AIDS-Related Malignancies" in MD Anderson Manual of Medical Oncology, (Kantarjian HM, Wolff RA, Koller CA, eds) McGraw-Hill Medical, New York, 2006, p.903-935

  16. Malignant Lymphoma, (Medline Plus; U.S. NLM and NIH), [], updated, 5/1/2006, Benjamin Taragin, M.S., Department of Radiology, Columbia Presbyterian Medical Center, New York, NY. Review by Verimed Healthcare Network, A.D.A.M.

  17. Slatery ML, Samowitz W, Curtin K, Khe NH, Hoffman M, Caasn B, Neuhausen S. Associations among IRS-1, IRS-2, IGF-I, and IGFBP3 Genetic Polymorphisms Colorectal Cancer, Cancer Epidemiol Biomarkers Prev 2004; 13(7), July, 2004.

    1. Singh P, Rubin N Insulinlike growth factors and binding proteins in colon cancer.  Gastroenterology,1993; 105: 1218-1237.

    2. Werner H, Le Roith D. The insulin like growth factor I receptor signaling pathways are important for tumorigenesis and inhibition of apoptosis. Crit Rev Oncog 1997; 8: 71-92.

    3. Sandhu MS, Dunger DB, Giovannucci EL.  Insulin, insulin-like growth factor-I (IGF-I), IGF binding proteins, their biological interactions and colorectal cancer. J. Natl Cancer Inst 2002; 94: 972-980.

  18. Borofsky ND, Vogelman JH, Krajcik RA, Orentreich N. Utility of insulin-like growth factor-1 as a biomarker in epidemiologic studies. Clinical Chemistry 48, No. 12, 2002.

    1. Yu H, Rohan R. Role of the insulin-like growth factor family in  cancer development and progression [Review] J Natl Cancer Inst 2000; 92: 1472-1489.

    2. Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson, P. et al. Plasma insulin-like growth factor and prostate cancer risk; a prospective study. Science 1998: 279: 563-566.

    3. Kraaks R, Toniolo P, Akhmedkhanov A, Lukanova A, Biessy et al.  Serum C-peptide, insulin like growth factor (IGF-I), IGF-binding proteins, and colorectal cancer risk in women. J Natl Cancer Inst 2002; 92: 1592-1600.

    4. Langlois JA, Rosen CJ, Viser M, Hannan MT, Harris T, Wilson PWF, et al. Association between insulin-like growth factor 1 and bone mineral density in older women and men: the Framingham  Heart Study. J. Clin Endocrinol Metab 1998; 83:4257-4262.

    5. Aleman A, Verhaar HJJ De Haan EHF, De Vries WR, Sampson MM, Drent ML et al. Insulin-like growth factor 1 and cognitive function in healthy older men.J Clin Endorinol Metab 1999; 84: 471-475.

    6. Janssen JAMJL, Stolk RP, Pols HAP, Grobbee DE, Lamberts SWJ. Serum total IGF-I, free IGF-I, and IGFBP1 levels in an elderly population.  Relation to cardiovascular risk factors and disease.Arterioscler Throm Vasc Biol 1998; 18:277-282.

  19. Chynoweth DP "Lecture 7. Principles and Methods of Biotechnology", University of Florida, Agricultural and Biological Engineering, .

  20. Medical Ecology: Stratospheric Ozone Depletion .

  21. Mitchell, D "DNA Damage and Repair" Ecology of UV .

  22. Strickland PT,  Kensler TW, "Environmental Factors" in Clinical Oncology, 3rd Edition (Abeloff MD, Armirtage, JO, Niederhuber, JE, Kastan MB, McKenna, WG, eds), Elsevier Churchill-Livingstone, Philadelphia, 2004, pp. 173-189.

  23. Chen CL, Hsu LI, Chiou HY, Hsueh YM, Chen SY, Wu MM, Chen CJ Ingested Arsenic, Cigarette Smoking, and Lung Cancer Risk:  A Follow-up Study in Arseniasis-Endemic Areas in Taiwan, JAMA, 2004;292:2984-2990.

  24. Chou WC, Hawkins AL, Barrett JF, Griffin CA, Dang, CV Arsenic Inhibition of Telomerase Transcription Leads to Genetic Instability. The Journal of Clinical Investigation, November 2001: 108(10), 1541-1547.

  25. Arsenic-based Medicine Visible Proofs:  Forensic Views of the Body, National Library of Medicine (

  26. Waisberg M, Joseph P, Hale B, Beyersmann D. Review:  "Molecular and cellular mechanisms of cadmium carcinogenesis" Toxicology 192(2-3) November 2003, pp 95-117.

  27. Wijnhoven BPL, Dinjens WNM, Pignatelli M Review:  "E-cadherin-catenin cell-cell adhesion complex and human cancer" British Journal of Surgery 87(8) 2000,  pp 992-1005

  28. Zoroddu MA, Schinocca L, Kowalik-Jankowska T, Kozlowski H, Salnikow K, Mosta M. Molecular Mechanisms in Nickel Carcinogenesis:  Modeling Ni(II) Binding Site in Histone H4. Environ. Health Perspect. Supplements 110(S5), October, 2002.

  29. Costa M, Yan Y, Zhao D, Sainikow K Molecular mechanisms of nickel carcinogenesis: Gene silencing by nickel delivery to the nucleus and gene activation/inactivation by nickel-induced cell signaling. J. Environ. Monit., 2003, 4, 222-223.

  30. Figure Griffiths et al (2004); text annotation by Steven M. Carr (2007)

  31. Norseth T "The carcinogenicity of chromium" Environ Health perspect (1981) 40: 121-131.

  32. O'Brien TJ, Ceryak S, Patierno SR Complexities of chromium carcinogenesis:  role of cellular response, repair and recovery mechanisms. Mutation Research/Fundamental and Molecular Mechanism of Mutagenesis 522(1-2) 2003, 3-36.

  33. Zhitkovich A, Quievryn G, Messer J, Motylevich Z Reductive Activation with Cysteine Represents a Chromium (III)-Dependent Pathway in the Induction Genotoxicity by Carcinogenic Chromium(VI), Environ. Health Perspect. Supplements 110(5) October 2002.

  34. Yang H, Bocchetta M, Kroczynska B, Elmishad AG, Chen Y, Liu Z, Bubici C, Mossman BT, Pass HI, Testa JR, Franzoso G, Carbone M. TNF-α inhibits asbostos-induced cytotoxicity via  a NF-κB-dependent pathway, a possible mechanims for asbestosis oncogenesis PNAS 103(27) 2006, pp 10397-10402.

  35. Gilmore TD The Rel/NF-kappaB Signal Transduction Pathway, .

  36. Strickland PT,  Kensler TW, Genesis of Cancer B: "Environmental Factors" in Clinical Oncology, 4th Edition (Abeloff MD, Armirtage, JO, Niederhuber, JE, Kastan MB, McKenna, WG, eds), Elsevier Churchill-Livingstone, Philadelphia, 2008, pp. 125-138.

  37. Wilbourne JD, McGregor DB, Partensky C, Rice JM IARC Reevaluates Silica and Related Substances, Environ. Health Perspect.  105(7) July, 1997.

  38. Dwyer D "How Quartz Watches Work, .

  39. Saffiotti U, Daniel LM, Mao Y, Shi X, Williams AO, Kaighn ME. Mechanism of carcinogenesis by crystalline silica in relation to oxygen radicals. Environ. Health Perspect. 1994 Dec. 102 Suppl 10: 159-63.

  40. Holmila R, Cyr D, Luce D, Heikkila P, Dictor M, Steiniche T, Stjernvall T, Bornholdt J, Wallin H, Wolff H, Husgafvel-Pursianen K. COX-2 and p53 in human sinonasal cancer:  COX-2 expression is associated with adenocarcinoma histology and wood-dust exposure, Int J Cancer. 2008 May 1; 122(9): 2154-2159.

  41. Smyth EM, FitzGerald GA The Eicosanoids:  Prostaglandins, Thromboxanes, Leukotrienes, and Related Compounds (in Basic and Clinical Pharmacology,10th edition, edited by Katzung,BG) McGraw-Hill Medical, Lange Series, New York, 2007, p 294.

  42. Selected Non-Heterocyclic Polycyclic Aromatic Hydrocarbons:  United Nations Environment Programme; International Labour Organization; World Health Organization; International Programme on Chemical Safety; Environmental Health Criteria 202; World Health Organization, Geneva, 1998

  43. Polycyclic Aromatic Hydrocarbons:  Toxicology [Information System for the Evaluation of Health Risks Associated with Occupational Exposure to Mutagens / Carcinogens;  Carcinogenic Risk in Occupational Settings, constructed and maintained by a collaborative effort of scientists from several Belgian Universities: KUL, RUG, UCL, ULg, VUB; 2008.

  44. Medical Pharmacology

  45. Jung I, Messing E Molecular Mechanisms and Pathways in Bladder Cancer Development and Progression Cancer Control 7(4) 2000 325-334.

  46. Kadlubar FF, Badawi AF Genetic Susceptibility and Carcinogen-DNA Adduct Formation in Human Urinary Bladder Carcinogenesis 1995; 82-83:627-632.

  47. Bostwick Laboratories Normal and Abnormal Urothelial Cells

  48. Yoon BL, Guang XL, Kitada K, Kawasaki, Y, Igarashi K, Kodama Y, Inoue T, Kobayashi K, Kanno J, Kim DY, Inoue T, Hirabayashi Y Mechanisms of benzene-induced hematoxicity and leukemogenicity:  cDNA microarray analyses using mouse bone marrow tissue-Toxicogenomics Environ Health Perspect 111: 1411-1420 (2003).

  49. Fenton RG, Longo DL Cancer Cell Biology and Angiogenesis in Harrison's Principles of Internal Medicine, 17th edition (Fauci AS, Braunwald E, Kasper DL, Hauser, SL, Longo DL, Jameson JL, Loscalzo J., eds) McGraw-Hill Medical, New York, pp. 498-513, 2008.

  50. Farazi PA, DePinho RA Hepatocellular carcinoma pathogenesis:  from genes to environment Nature Reviews Cancer 6, 674-687 (September 2006).

  51. CDC Ajello L, Aspergillus flavus .

  52. Groopman JD, Sidney Aflatoxin and hepatocellular carcinoma (Liver Cancer), Kimmel Comprehensive Cancer Center, Johns Hopkins University,  Interview sponsored by the AACR (American Association for Cancer Research) .

  53. Siegel A Bladder Cancer (Part 1 of 2) .

  54. Siegel A Bladder Cancer (Part 2 of 2) .

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