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Screening of molecular cell targets for carcinogenic heterocyclic aromatic amines by using CALUX® reporter gene assays

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Abstract

Heterocyclic aromatic amines (HCAs) are compounds formed when meat or fish are cooked at high temperatures for a long time or over an open fire. To determine which pathways of toxicity are activated by HCAs, nine out of the ten HCAs known to be carcinogenic in rodents (2-amino-9H-pyrido[2,3-b]indole (AαC), 2-aminodipyrido[1,2-a:3′,2-d]imidazole (Glu-P-2), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAαC), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2)) were tested in the estrogen receptor α (ERα), androgen receptor (AR), glucocorticoid receptor (GR), peroxisome proliferator-activated receptor γ2 (PPARγ2), polycyclic aromatic hydrocarbons (PAH), Nrf2, and p53 CALUX® reporter gene assays. Trp-P-1 was the only HCA that led to a positive response in the ERα, PPARγ2, and Nrf2 CALUX® assays. In the PAH CALUX® assay, Trp-P-2, MeAαC, and AαC induced luciferase activity to a greater extent than MeIQ and PhIP. In the p53 CALUX® assay without a coupled metabolic activation, only Trp-P-1 and Trp-P-2 enhanced luciferase expression; when a metabolic activation step was coupled to the p53 CALUX® assay, Trp-P-1, Glu-P-2, MeIQ, MeIQx, and PhIP induced a positive response. No HCA was positive in the AR and GR CALUX® assays. Taken together, the results obtained show that the battery of CALUX® assays performed in the present study can successfully be used to screen for molecular cell targets of carcinogenic compounds such as HCAs.

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Abbreviations

AαC:

2-Amino-9H-pyrido[2,3-b]indole

BCRP:

Breast cancer resistance protein

Glu-P-2:

2-Aminodipyrido[1,2-a:3′,2-d]imidazole

HCAs:

Heterocyclic aromatic amines

IQ:

2-Amino-3-methylimidazo[4,5-f]quinoline

MeAαC:

2-Amino-3-methyl-9H-pyrido[2,3-b]indole

MeIQ:

2-Amino-3,4-dimethylimidazo[4,5-f]quinoline

MeIQx:

2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline

PhIP:

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

Trp-P-1:

3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole

Trp-P-2:

3-Amino-1-methyl-5H-pyrido[4,3-b]indole

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  1. Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Bischofsholer Damm 15, 30173, Hannover, Germany

    Pablo Steinberg

  2. BioDetection Systems, Science Park 406, 1098XH, Amsterdam, The Netherlands

    Peter A. Behnisch, Harrie Besselink & Abraham A. Brouwer

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Steinberg, P., Behnisch, P.A., Besselink, H. et al. Screening of molecular cell targets for carcinogenic heterocyclic aromatic amines by using CALUX® reporter gene assays. Cell Biol Toxicol 33, 283–293 (2017). https://doi.org/10.1007/s10565-016-9373-6

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