Role of human sulfotransferase 1A1 and N-acetyltransferase 2 in the metabolic activation of 16 heterocyclic amines and related heterocyclics to genotoxicants in recombinant V79 cells.
Heterocyclic aromatic amines (HAAs) are primarily produced during the heating of meat or fish. HAAs are mutagenic and carcinogenic, and their toxicity in model systems depend on metabolic activation. This activation is mediated by cytochrome P450 (CYP) enzymes, in particular CYP1A2. Some studies have indicated a role of human sulfotransferase (SULT) 1A1 and N-acetyltransferase (NAT) 2 in the terminal activation of HAAs. In this study, we conducted a metabolism/genotoxicity relationship analysis for 16 HAAs and related heterocyclics. We used the γH2AX genotoxicity assay in V79 cells (deficient in CYP, SULT and NAT) and V79-derived cell lines genetically engineered to express human CYP1A2 alone or in combination with human SULT1A1 or NAT2. Our data demonstrated genotoxic properties for 13 out of the 16 compounds tested. A clear relationship between metabolic bioactivation and genotoxicity allowed to distinguish four groups: (1) Trp-P-1 genotoxicity was linked to CYP1A2 bioactivation only-with negligible effects of phase II enzymes; (2) Glu-P-2, Glu-P-1, Trp-P-2, APNH, MeAαC and AαC were bioactivated by CYP1A2 in combination with either phase II enzyme tested (NAT2 or SULT1A1); (3) IQ, 4-MeIQ, IQx, 8-MeIQx, and 4,8-DiMeIQx required CYP1A2 in combination with NAT2 to be genotoxic, whereas SULT1A1 did not enhance their genotoxicity; (4) PhIP became genotoxic after CYP1A2 and SULT1A1 bioactivation-NAT2 had not effect. Our results corroborate some previous data regarding the genotoxic potency of seven HAAs and established the genotoxicity mechanism for five others HAAs. This study also permits to compare efficiently the genotoxic potential of these 13 HAAs.
Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA-UMR1331, ENVT, INP-Purpan, UPS, Toxalim, 180 chemin de Tournefeuille BP 93173, 31027, Toulouse Cedex 3, France.
Matthieu
M
Chevereau
Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE), 14558, Nuthetal, Germany.|Department of Food Safety, Federal Institute for Risk Assessment, Max-Dohrn-Strasse 8-10, 10589, Berlin, Germany.
Hansruedi
H
Glatt
Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA-UMR1331, ENVT, INP-Purpan, UPS, Toxalim, 180 chemin de Tournefeuille BP 93173, 31027, Toulouse Cedex 3, France.
Daniel
D
Zalko
Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA-UMR1331, ENVT, INP-Purpan, UPS, Toxalim, 180 chemin de Tournefeuille BP 93173, 31027, Toulouse Cedex 3, France.
Jean-Pierre
JP
Cravedi
Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA-UMR1331, ENVT, INP-Purpan, UPS, Toxalim, 180 chemin de Tournefeuille BP 93173, 31027, Toulouse Cedex 3, France. marc.audebert@inra.fr.
Marc
M
Audebert
D065767:Activation, Metabolic; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D015239:Arylsulfotransferase / Q000235:genetics / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics* / Q000633:toxicity; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens / Q000493:pharmacokinetics; D011810:Quinoxalines / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D006571:Heterocyclic Compounds; D007093:Imidazoles; D009153:Mutagens; D011810:Quinoxalines; D011994:Recombinant Proteins; C023785:2-amino-6-methyldipyrido(1,2-a-3',2'-d)imidazole; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human
Genotoxicity; H2AX; Heterocyclic aromatic amines; Metabolism; V79 cells