Oncotarget

Research Papers:

Identification of cancer chemopreventive isothiocyanates as direct inhibitors of the arylamine N-acetyltransferase-dependent acetylation and bioactivation of aromatic amine carcinogens

Romain Duval, Ximing Xu, Linh-Chi Bui, Cécile Mathieu, Emile Petit, Kevin Cariou, Robert H. Dodd, Jean-Marie Dupret and Fernando Rodrigues-Lima _

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Oncotarget. 2016; 7:8688-8699. https://doi.org/10.18632/oncotarget.7086

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Abstract

Romain Duval1, Ximing Xu1, Linh-Chi Bui1, Cécile Mathieu1, Emile Petit1, Kevin Cariou2, Robert H. Dodd2, Jean-Marie Dupret1,3, Fernando Rodrigues-Lima1,3

1Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France

2Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Saclay, 91198 Gif-sur-Yvette, France

3UFR Sciences du Vivant, Université Paris Diderot, 75013 Paris, France

Correspondence to:

Fernando Rodrigues-Lima, e-mail: fernando.rodrigues-lima@univ-paris-diderot.fr

Keywords: cancer chemoprevention, arylamine carcinogens, isothiocyanate phytochemicals, carcinogen metabolism, enzyme inhibition

Received: October 06, 2015     Accepted: January 15, 2016     Published: January 30, 2016

ABSTRACT

Aromatic amines (AAs) are chemicals of industrial, pharmacological and environmental relevance. Certain AAs, such as 4-aminobiphenyl (4-ABP), are human carcinogens that require enzymatic metabolic activation to reactive chemicals to form genotoxic DNA adducts. Arylamine N-acetyltransferases (NAT) are xenobiotic metabolizing enzymes (XME) that play a major role in this carcinogenic bioactivation process. Isothiocyanates (ITCs), including benzyl-ITC (BITC) and phenethyl-ITC (PEITC), are phytochemicals known to have chemopreventive activity against several aromatic carcinogens. In particular, ITCs have been shown to modify the bioactivation and subsequent mutagenicity of carcinogenic AA chemicals such as 4-ABP. However, the molecular and biochemical mechanisms by which these phytochemicals may modulate AA carcinogens bioactivation and AA-DNA damage remains poorly understood.

This manuscript provides evidence indicating that ITCs can decrease the metabolic activation of carcinogenic AAs via the irreversible inhibition of NAT enzymes and subsequent alteration of the acetylation of AAs. We demonstrate that BITC and PEITC react with NAT1 and inhibit readily its acetyltransferase activity (ki = 200 M−1.s−1 and 66 M−1.s−1 for BITC and PEITC, respectively). Chemical labeling, docking approaches and substrate protection assays indicated that inhibition of the acetylation of AAs by NAT1 was due to the chemical modification of the enzyme active site cysteine. Moreover, analyses of AAs acetylation and DNA adducts in cells showed that BITC was able to modulate the endogenous acetylation and bioactivation of 4-ABP. In conclusion, we show that direct inhibition of NAT enzymes may be an important mechanism by which ITCs exert their chemopreventive activity towards AA chemicals.


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