The role of metabolic activation by cytochrome P-450 in covalent binding of VP 16-213 to rat liver and HeLa cell microsomal proteins

J. M S van Maanen, C. de Ruiter, J. de Vries, P. R. Kootstra, F. Gobas, H. M. Pinedo

Research output: Contribution to journalArticlepeer-review

Abstract

Covalent binding of 3H-labeled VP 16-213 to rat liver and HeLa cell microsomal proteins was studied in vitro. Metabolic activation by cytochrome P-450 was found to play a role in the covalent binding of VP 16-213 to rat liver microsomal proteins, as shown by the need of NADPH cofactor, the increased binding after phenobarbital pretreatment and the inhibition by SFK-525A. Addition of ascorbic acid or α-phenyl-N-tert. butylnitrone to the incubation mixture depressed covalent binding by about 85%, suggesting that formation of a reactive metabolite from the phenolic structure may be involved in the binding process. VP 16-213 did not inhibit aminopyrine N-demethylase at the concentration used in the binding experiments (17 μM), indicating that metabolism of its methylenedioxy group does not play a role in binding to microsomal proteins. HeLa cell microsomes were found to possess aminopyrine N-demethylase activity. Covalent binding of radiolabeled VP 16-213 to HeLa cell microsomes decreased by about 64% if NADPH was omitted.

Original languageEnglish (US)
Pages (from-to)1099-1106
Number of pages8
JournalEuropean Journal of Cancer and Clinical Oncology
Volume21
Issue number9
DOIs
StatePublished - 1985
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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