Differential toxicity of heterocyclic aromatic amines and their mixture in metabolically competent HepaRG cells.

Abstract

Human exposure to heterocyclic aromatic amines (HAA) usually occurs through mixtures rather than individual compounds. However, the toxic effects and related mechanisms of co-exposure to HAA in humans remain unknown. We compared the effects of two of the most common HAA, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), individually or in combination, in the metabolically competent human hepatoma HepaRG cells. Various endpoints were measured including cytotoxicity, apoptosis, oxidative stress and DNA damage by the comet assay. Moreover, the effects of PhIP and/or MeIQx on mRNA expression and activities of enzymes involved in their activation and detoxification pathways were evaluated. After a 24h treatment, PhIP and MeIQx, individually and in combination, exerted differential effects on apoptosis, oxidative stress, DNA damage and cytochrome P450 (CYP) activities. Only PhIP induced DNA damage. It was also a stronger inducer of CYP1A1 and CYP1B1 expression and activity than MeIQx. In contrast, only MeIQx exposure resulted in a significant induction of CYP1A2 activity. The combination of PhIP with MeIQx induced an oxidative stress and showed synergistic effects on apoptosis. However, PhIP-induced genotoxicity was abolished by a co-exposure with MeIQx. Such an inhibitory effect could be explained by a significant decrease in CYP1A2 activity which is responsible for PhIP genotoxicity. Our findings highlight the need to investigate interactions between HAA when assessing risks for human health and provide new insights in the mechanisms of interaction between PhIP and MeIQx.

• Authors: Julie Dumont, Rozenn Jossé, Carine Lambert, Sébastien Anthérieu, Ludovic Le Hegarat, Caroline Aninat, Marie-Anne Robin, Christiane Guguen-Guillouzo, André Guillouzo
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 245 Issue 2 Pg. 256-63 (Jun 01 2010) ISSN: 1096-0333 [Electronic] United States
• PMID: 20307560 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2010 Elsevier Inc. All rights reserved.

Chemical References

• Imidazoles
• Quinoxalines
• 2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline
• Cytochrome P-450 Enzyme System
• 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine

Topics

• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cytochrome P-450 Enzyme System (metabolism)
• DNA Damage
• Dose-Response Relationship, Drug
• Humans
• Imidazoles (toxicity)
• Oxidative Stress (drug effects)
• Polymerase Chain Reaction
• Quinoxalines (toxicity)