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Effects of harman and norharman on the metabolism and genotoxicity of 2-acetylaminofluorene in cultured rat hepatocytes

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Monolayers of rat hepatocytes metabolize 0.25 m M 2-acetylaminofluorene (AAF) to various ether-extractable, water-soluble as well as covalently bound products. The major ether-extractable metabolite formed is 2-aminofuorene (AF), followed by 7-OH-AAF and 9-OH-AAF. Pretreatment of rats with the inducer Aroclor 1254 (PCB) increased the metabolism of AAF and caused an increased DNA repair synthesis in hepatocytes exposed to AAF or AF. With N-OH-AAF, a decreased genotoxic response in PCB-treated cells compared to control cells was seen. The addition of harman and norharman decreased the metabolism of AAF to ether-extractable metabolites, water-soluble metabolites and metabolites covalently bound to macromolecules. In contrast, the DNA-repair synthesis caused by the same concentrations of AAF was increased by harman. One explanation for this apparent discrepancy could be that the aromatic amines changed the metabolism of harman and norharman in such a way that these compounds were converted into genotoxic metabolites.

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Abbreviations

AAF:

2-acetylaminofluorene

AF:

2-aminofluorene

DMSO:

dimethylsulfoxide

HPLC:

high performance liquid chromatography

N-OH-AAF:

N-ydroxy-2-acetylaminofluorene

PCB:

polychlorinated biphenyls, Aroclor 1254

TCDD:

2,3,7,8-tetrachlorodibenzo-p-dioxin

TdR:

thymidine

Trp-P-1:

3-amino-1,4dimethyl-5H-pyrido(4,3b)indole

Trp-P-2:

3-amino-l-methyl-5H-pyrido(4,3b)indole

UDS:

unscheduled DNA synthesis

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  1. Department of Toxicology, National Institute of Public Health, Oslo, Norway

    Jørn A. Holme, Erik Søderlund & Tore Aune

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  1. Jørn A. Holme
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  2. Erik Søderlund
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Holme, J.A., Søderlund, E. & Aune, T. Effects of harman and norharman on the metabolism and genotoxicity of 2-acetylaminofluorene in cultured rat hepatocytes. Cell Biol Toxicol 1, 223–239 (1985). https://doi.org/10.1007/BF00120166

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