Cytochrome P-450-mediated O-demethylation: A route in the metabolic activation of etoposide (VP-16-213)

J. M S van Maanen, J. de Vries, D. Pappie, E. van den Akker, V. M. Lafleur, J. Retèl, J. van der Greef, H. M. Pinedo

Research output: Contribution to journalArticlepeer-review

Abstract

The antitumor agent VP-16-213 is oxidatively O-demethylated by rat liver microsomes and purified rat liver microsomal P-450. 3-Methylcholanthrene can quantitatively induce O-demethylation of VP-16-213. The K(m) and V(max) values for O-demethylation by noninduced, phenobarbital-, and 3-methylcholanthrene-induced rat liver microsomes were found to be 130, 600, and 160 μM and 8.5, 11.8, and 15.6 nmol H2CO/min·mg protein, respectively. Mass spectrometric comparison of the product of O-demethylation of VP-16-213 with the synthetic metabolite resulted in identification of the orthodihydroxy derivative. In studies on the biological activity of the orthodihydroxy derivative, it was found to inactivate single- and double-stranded ΦX174 DNA, to bind to calf thymus DNA and to be highly toxic against chinese hamster ovary cells.

Original languageEnglish (US)
Pages (from-to)4658-4662
Number of pages5
JournalCancer Research
Volume47
Issue number17
StatePublished - 1987
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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