Bioactivation of 2-nitrofluorene to reactive intermediates that bind covalently to DNA, RNA and protein in vitro and in vivo in the rat.

Abstract:

:The activation of 2-nitrofluorene (2-NF) to reactive intermediates that bind covalently to DNA, RNA and protein has been investigated both in vitro and in the rat in vivo. In vitro, such binding was catalyzed by the hepatic microsomal fraction, was NADPH dependent and could be inhibited by SKF 525A, an inhibitor of cytochrome P450. The generation of reactive intermediates therefore is most likely catalyzed by cytochrome P450. Covalent binding of 2-NF could not be prevented by glutathione, N-acetylcysteine and other thiol-containing compounds. It could be partially prevented by guanosine, presumably because it traps the reactive intermediate(s). Under normal oxygenation conditions 2-NF was also covalently bound in freshly isolated hepatocytes; pretreatment of rats with an inducer of cytochrome P450, Aroclor 1254, gave rise to a higher rate of covalent binding in hepatocytes. Covalent binding of 2-NF to cellular macromolecules also occurred in vivo, both after oral and i.v. administration. Pentachlorophenol, a selective sulfation inhibitor, did not influence the covalent binding of 2-NF; therefore, the reactive intermediate is not formed by sulfation of N-hydroxy-2-acetylaminofluorene, which could be a metabolite of 2-NF. It is concluded that the reactive intermediates most likely can be formed from 2-NF by the cytochrome P450 enzyme system.

journal_name

Carcinogenesis

journal_title

Carcinogenesis

authors

Wierckx FC,Wedzinga R,Meerman JH,Mulder GJ

doi

10.1093/carcin/11.1.27

subject

Has Abstract

pub_date

1990-01-01 00:00:00

pages

27-32

issue

1

eissn

0143-3334

issn

1460-2180

journal_volume

11

pub_type

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