Skip to main content
SpringerLink
Log in

6-methylhydroxylation of the anti-cancer agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by flavin-containing monooxygenase 3

  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Summary

The involvement of flavin-containing monooxygenase (FMO) in the 6-methylhydroxylation of the experimental anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA) was investigated by use of human liver microsomes and microsomes containing cDNA-expressed FMOs. The involvement of FMO in the formation of 6-methyl hydroxylate of DMXAA, 6-hydroxymethyl-5-methylxanthenone-4-acetic acid (6-OH-MXAA) in human liver microsomes was indicated by the fact that this biotransformation was sensitive to heat treatment, increased at pH 8.3, and inhibited by methimazole. Only FMO3 formed 6-OH-MXAA at a similar rate to that in cDNA-expressed cytochromes P-450 (CYP)1A2. The results of this study indicate that human FMO3 has the capacity to form 6-OH-MXAA, but plays a lesser important role for this reaction than CYP1A2 that has been demonstrated to catalyse 6-OH-MXAA formation.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

CYP:

cytochrome P-450

DMXAA:

5,6-dimethylxanthenone-4-acetic acid

FMO:

flavin-containing monooxygenase

HPLC:

high performance liquid chromatography

6-OH-MXAA:

6-hydroxymethyl-5-methylxanthenone-4-acetic acid.

References

  1. Cashman JR (1995) Structural and catalytic properties of the mammalian flavin-containing monooxygenase. Chem Res Toxicol 8: 165–181.

    Article  CAS  Google Scholar 

  2. Hines RN, Cashman JR, Philpot RM, Williams DE and Ziegler DM (1994) The mammalian flavin-containing monooxygenases: Molecular characterization and regulation of expression. Toxicol Appl Pharmacol 125: 1–6.

    Article  PubMed  CAS  Google Scholar 

  3. Kestell P, Paxton JW, Rewcastle GW, Dunlop I and Baguley BC (1999) Plasma disposition, metabolism and excretion of the experimental antitumour agent 5,6-dimethylxanthenone-4-acetic acid in the mouse, rat and rabbit. Cancer Chemother Pharmacol 43: 323–330.

    Article  PubMed  CAS  Google Scholar 

  4. Miners JO, Valente L, Lillywhite KJ, Mackenzie PI, Burchell B, Baguley BC and Kestell P (1997) Preclinical prediction of factors influencing the elimination of 5,6-dimethylxanthenone-4acetic acid, a new anticancer drug. Cancer Res 57: 284–289.

    PubMed  CAS  Google Scholar 

  5. Omura T and Sato R (1964) The carbon monoxide binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J Biol Chem 23: 2370–2378.

    Google Scholar 

  6. Phillips IR, Dolphin CT, Clair P, Hadley MR, Hutt AJ, McCombie RR, Smith RL and Shephard EA (1995) The molecular biology of the flavincontaining monooxygenases of man. Chem-Biol Interact 96: 17–32.

    Article  PubMed  CAS  Google Scholar 

  7. Rewcastle GW, Atwell GI, Li ZA, Baguley BC and Denny WA (1991) Potential antitumour agents. 61. Structure-activity relationships for inn vivo colon 38 activity among disubstituted 9-oxo-9H-xanthenone-4-acetic acids. J Med Chem 34: 217–222.

    Article  PubMed  CAS  Google Scholar 

  8. Rewcastle GW, Kestell P, Baguley BC and Denny WA (1990) Light-induced breakdown of flavone acetic acid and xanthenone analogues in solution. J Natl Cancer Inst 82: 528–529.

    Article  PubMed  CAS  Google Scholar 

  9. Ring BJ, Wrighton SA, Aldridge SL, Hansen K, Haehner B and Shipley LA (1999) Flavin-containing monooxygenase-mediated N-oxidation of the M(1)-muscarinic agonist xanomeline. Drug Metab Dispos 27: 1099–1103.

    PubMed  CAS  Google Scholar 

  10. Robson RA, Mathews AP, Miners JO, McManus ME, Meyer UA, Hall PD, Birkett DJ (1987) Characterisation of theophylline metabolism by human liver microsomes. Br J Clin Pharmacol 24: 293–300.

    PubMed  CAS  Google Scholar 

  11. Smith PK, Krohn RI, Hermanson GT, Mallia AK, Garter FH, Provenzano MD, Fujimoto EK, Goeke NM, Olson BJ and Klenk DC (1985) Measurement of protein using bicinchoninic acid. Anal Biochem 150: 76–85.

    Article  PubMed  CAS  Google Scholar 

  12. Webster LK, Ellis AG, Kestell P and Rewcastle GW (1995) Metabolism and elimination of 5,6-dimethylxanthenone-4-acetic acid in the isolated perfused rat liver. Drug Metab Dispos 23: 363–368.

    PubMed  CAS  Google Scholar 

  13. Zhou SF, Paxton JW, Tingle MD, McCall J and Kestell P (1999) Determination of two major metabolites of the novel anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid in hepatic microsomal incubations by high-performance liquid chromatography with fluorescennce detection. J Chromatogr (B) 734: 129–136.

    Article  CAS  Google Scholar 

  14. Zhou SF, Paxton JW, Tingle MD and Kestell P (2000) Identification of the human liver cytochrome P450 isozyme responsible for the 6-methylhydroxylation of the novel anticancer drug 5,6-dimethylxanthenone-4-acetic acid. Drug Metab Dispos 28: 1449–1456.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Auckland Cancer Society Research Centre, The University of Auckland, Auckland, New Zealand

    Philip Kestell

  2. Division of Pharmacology and Clinical Pharmacology Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand

    Shufeng Zhou PhD. & James W. Paxton

Authors
  1. Shufeng Zhou PhD.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philip Kestell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James W. Paxton
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhou, S., Kestell, P. & Paxton, J.W. 6-methylhydroxylation of the anti-cancer agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by flavin-containing monooxygenase 3. Eur. J. Drug Metab. Pharmacokinet. 27, 179–183 (2002). https://doi.org/10.1007/BF03190455

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03190455

Keywords

Search

Navigation