title: Identification of cancer chemopreventive isothiocyanates as direct inhibitors of the arylamine N-acetyltransferase-dependent acetylation and bioactivation of aromatic amine carcinogens.
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 (k(i) = 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.
authors: Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France.
authors: Romain
authors: R
authors: Duval
authors: Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France.
authors: Ximing
authors: X
authors: Xu
authors: Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France.
authors: Linh-Chi
authors: LC
authors: Bui
authors: Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France.
authors: Cécile
authors: C
authors: Mathieu
authors: Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France.
authors: Emile
authors: E
authors: Petit
authors: Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Saclay, 91198 Gif-sur-Yvette, France.
authors: Kevin
authors: K
authors: Cariou
authors: Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Saclay, 91198 Gif-sur-Yvette, France.
authors: Robert H
authors: RH
authors: Dodd
authors: Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France.|UFR Sciences du Vivant, Université Paris Diderot, 75013 Paris, France.
authors: Jean-Marie
authors: JM
authors: Dupret
authors: Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France.|UFR Sciences du Vivant, Université Paris Diderot, 75013 Paris, France.
authors: Fernando
authors: F
authors: Rodrigues-Lima
mesh_terms: D000107:Acetylation; D000588:Amines / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000037:antagonists & inhibitors*; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D002273:Carcinogens / Q000633:toxicity*; D018736:DNA Adducts / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D007700:Kinetics; D014407:Tumor Cells, Cultured
chemical_list: D000588:Amines; D002273:Carcinogens; D018736:DNA Adducts; D004791:Enzyme Inhibitors; D017879:Isothiocyanates; C058305:phenethyl isothiocyanate; C031403:benzyl isothiocyanate; D001191:Arylamine N-Acetyltransferase
keywords: arylamine carcinogens; cancer chemoprevention; carcinogen metabolism; enzyme inhibition; isothiocyanate phytochemicals