Skip to main content
SpringerLink
Log in

Systems Biology Approaches to Enzyme Kinetics

  • Protocol
  • First Online:
Enzyme Kinetics in Drug Metabolism

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2342))

Abstract

Intracellular drug metabolism involves transport, bioactivation, conjugation, and other biochemical steps. The dynamics of these steps are each dependent on a number of other cellular factors that can ultimately lead to unexpected behavior. In this review, we discuss the confounding processes and coupled reactions within bioactivation networks that require a systems-level perspective in order to fully understand the time-varying behavior. When converting known in vitro characteristics of drug-enzyme interactions into descriptions of cellular systems, features such as substrate availability, cell-to-cell variability, and intracellular redox state, deserve special focus. Two examples are provided. First, a model of hydrogen peroxide clearance during chemotherapy treatment serves as a basis to discuss an example of sensitivity analysis. Second, an example of doxorubicin bioactivation is used for discussing points of consideration when constructing and analyzing network models of drug metabolism.

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

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 379.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Scheer M, Grote A, Chang A, Schomburg I, Munaretto C, Rother M, Sohngen C, Stelzer M, Thiele J, Schomburg D (2011) BRENDA, the enzyme information system in 2011. Nucleic Acids Res 39(Database issue):D670–D676. https://doi.org/10.1093/nar/gkq1089

    Article  CAS  PubMed  Google Scholar 

  2. Garfinkel D (1966) The digital computer as a biochemical instrument: simulation of milti-enzyme systems. Biochem Soc Symp 26:81–102

    CAS  PubMed  Google Scholar 

  3. Karr JR, Sanghvi JC, Macklin DN, Gutschow MV, Jacobs JM, Bolival B Jr, Assad-Garcia N, Glass JI, Covert MW (2012) A whole-cell computational model predicts phenotype from genotype. Cell 150(2):389–401. https://doi.org/10.1016/j.cell.2012.05.044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Alon U (2006) An introduction to systems biology: design principles of biological circuits. Chapman and Hall/CRC, Boca Raton, FL

    Book  Google Scholar 

  5. Voit EO (2012) A first course in systems biology. Garland Science, New York, NY

    Book  Google Scholar 

  6. Schnell S, Turner TE (2004) Reaction kinetics in intracellular environments with macromolecular crowding: simulations and rate laws. Prog Biophys Mol Biol 85(2-3):235–260. https://doi.org/10.1016/j.pbiomolbio.2004.01.012

    Article  CAS  PubMed  Google Scholar 

  7. Kholodenko BN, Sakamoto N, Puigjaner J, Westerhoff HV, Cascante M (1996) Strong control on the transit time in metabolic channelling. FEBS Lett 389(2):123–125

    Article  CAS  PubMed  Google Scholar 

  8. Cooper AJ, Bruschi SA, Anders MW (2002) Toxic, halogenated cysteine S-conjugates and targeting of mitochondrial enzymes of energy metabolism. Biochem Pharmacol 64(4):553–564

    Article  CAS  PubMed  Google Scholar 

  9. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC (1987) Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A 84(21):7735–7738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL, Chang G (2009) Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323(5922):1718–1722. https://doi.org/10.1126/science.1168750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lee CG, Gottesman MM, Cardarelli CO, Ramachandra M, Jeang KT, Ambudkar SV, Pastan I, Dey S (1998) HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter. Biochemistry 37(11):3594–3601. https://doi.org/10.1021/bi972709x

    Article  CAS  PubMed  Google Scholar 

  12. Ramachandra M, Ambudkar SV, Chen D, Hrycyna CA, Dey S, Gottesman MM, Pastan I (1998) Human P-glycoprotein exhibits reduced affinity for substrates during a catalytic transition state. Biochemistry 37(14):5010–5019. https://doi.org/10.1021/bi973045u

    Article  CAS  PubMed  Google Scholar 

  13. Lam FC, Liu R, Lu P, Shapiro AB, Renoir JM, Sharom FJ, Reiner PB (2001) beta-Amyloid efflux mediated by p-glycoprotein. J Neurochem 76(4):1121–1128

    Article  CAS  PubMed  Google Scholar 

  14. Lotz C, Kelleher DK, Gassner B, Gekle M, Vaupel P, Thews O (2007) Role of the tumor microenvironment in the activity and expression of the p-glycoprotein in human colon carcinoma cells. Oncol Rep 17(1):239–244

    CAS  PubMed  Google Scholar 

  15. McRae MP, Brouwer KL, Kashuba AD (2003) Cytokine regulation of P-glycoprotein. Drug Metab Rev 35(1):19–33. https://doi.org/10.1081/DMR-120018247

    Article  CAS  PubMed  Google Scholar 

  16. Prasanphanich AF, White DE, Gran MA, Kemp ML (2016) Kinetic modeling of ABCG2 transporter heterogeneity: a quantitative, single-cell analysis of the side population assay. PLoS Comput Biol 12(11):e1005188. https://doi.org/10.1371/journal.pcbi.1005188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Watson WH, Chen Y, Jones DP (2003) Redox state of glutathione and thioredoxin in differentiation and apoptosis. Biofactors 17(1-4):307–314

    Article  CAS  PubMed  Google Scholar 

  18. Holmgren A (1985) Thioredoxin. Annu Rev Biochem 54:237–271. https://doi.org/10.1146/annurev.bi.54.070185.001321

    Article  CAS  PubMed  Google Scholar 

  19. Schafer FQ, Buettner GR (2001) Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med 30(11):1191–1212

    Article  CAS  PubMed  Google Scholar 

  20. Humphries KM, Szweda PA, Szweda LI (2006) Aging: a shift from redox regulation to oxidative damage. Free Radic Res 40(12):1239–1243. https://doi.org/10.1080/10715760600913184

    Article  CAS  PubMed  Google Scholar 

  21. Aguiar M, Masse R, Gibbs BF (2005) Regulation of cytochrome P450 by posttranslational modification. Drug Metab Rev 37(2):379–404. https://doi.org/10.1081/dmr-46136

    Article  CAS  PubMed  Google Scholar 

  22. Terrados N, Jansson E, Sylven C, Kaijser L (1990) Is hypoxia a stimulus for synthesis of oxidative enzymes and myoglobin? J Appl Physiol 68(6):2369–2372

    Article  CAS  PubMed  Google Scholar 

  23. Mori K, Shibanuma M, Nose K (2004) Invasive potential induced under long-term oxidative stress in mammary epithelial cells. Cancer Res 64(20):7464–7472

    Article  CAS  PubMed  Google Scholar 

  24. Saltelli A, Tarantola S, Campolongo F (2000) Sensitivity analysis as an ingredient of modeling. Stat Sci 15(4):377–395

    Google Scholar 

  25. Fang S, Gertner GZ, Shinkareva S, Wang G, Anderson A (2003) Improved generalized Fourier amplitude sensitivity test (FAST) for model assessment. Stat Comput 13(3):221–226. https://doi.org/10.1023/a:1024266632666

    Article  Google Scholar 

  26. Bey EA, Reinicke KE, Srougi MC, Varnes M, Anderson VE, Pink JJ, Li LS, Patel M, Cao L, Moore Z, Rommel A, Boatman M, Lewis C, Euhus DM, Bornmann WG, Buchsbaum DJ, Spitz DR, Gao J, Boothman DA (2013) Catalase abrogates beta-lapachone-induced PARP1 hyperactivation-directed programmed necrosis in NQO1-positive breast cancers. Mol Cancer Ther 12(10):2110–2120. https://doi.org/10.1158/1535-7163.MCT-12-0962

    Article  CAS  PubMed  Google Scholar 

  27. Adimora NJ, Jones DP, Kemp ML (2010) A model of redox kinetics implicates the thiol proteome in cellular hydrogen peroxide responses. Antioxid Redox Signal 13(6):731–743. https://doi.org/10.1089/ars.2009.2968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cao L, Li LS, Spruell C, Xiao L, Chakrabarti G, Bey EA, Reinicke KE, Srougi MC, Moore Z, Dong Y, Vo P, Kabbani W, Yang CR, Wang X, Fattah F, Morales JC, Motea EA, Bornmann WG, Yordy JS, Boothman DA (2014) Tumor-selective, futile redox cycle-induced bystander effects elicited by NQO1 bioactivatable radiosensitizing drugs in triple-negative breast cancers. Antioxid Redox Signal 21(2):237–250. https://doi.org/10.1089/ars.2013.5462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Madssen TS, Cao MD, Pladsen AV, Ottestad L, Sahlberg KK, Bathen TF, Giskeodegard GF (2019) Historical biobanks in breast cancer metabolomics—challenges and opportunities. Meta 9(11). https://doi.org/10.3390/metabo9110278

  30. Finn NA, Findley HW, Kemp ML (2011) A switching mechanism in doxorubicin bioactivation can be exploited to control doxorubicin toxicity. PLoS Comput Biol 7(9):e1002151. https://doi.org/10.1371/journal.pcbi.1002151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kostrzewa-Nowak D, Paine MJ, Wolf CR, Tarasiuk J (2005) The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60-sensitive cell line and its multidrug-resistant sublines. Br J Cancer 93(1):89–97. https://doi.org/10.1038/sj.bjc.6602639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Finn NA, Kemp ML (2012) Pro-oxidant and antioxidant effects of N-acetylcysteine regulate doxorubicin-induced NF-kappa B activity in leukemic cells. Mol BioSyst 8(2):650–662. https://doi.org/10.1039/c1mb05315a

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA

    Nnenna A. Finn, Andrew D. Raddatz & Melissa L. Kemp

Authors
  1. Nnenna A. Finn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew D. Raddatz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Melissa L. Kemp
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Melissa L. Kemp .

Editor information

Editors and Affiliations

  1. Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, USA

    Swati Nagar

  2. Translational Medicine, Novartis Institutes for Biomedical Research, Inc., Cambridge, MA, USA

    Upendra A. Argikar

  3. Independent, Harleysville, PA, USA

    Donald Tweedie

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Finn, N.A., Raddatz, A.D., Kemp, M.L. (2021). Systems Biology Approaches to Enzyme Kinetics. In: Nagar, S., Argikar, U.A., Tweedie, D. (eds) Enzyme Kinetics in Drug Metabolism. Methods in Molecular Biology, vol 2342. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1554-6_15

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-1554-6_15

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1553-9

  • Online ISBN: 978-1-0716-1554-6

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation