Editor's Choice for December 2016

The December 2016 Editor's Choice article is "Human T Lymphocytes Bioactivate Heterocyclic Aromatic Amines by Forming DNA Adducts" by Medjda Bellamri, Ludovic Le Hegarat, Laurent Vernhet, Georges Baffet, Robert J. Turesky, and Sophie Langouët.

Heterocyclic aromatic amines (HAA) comprise an important class of potential human carcinogens, formed in meat and fish cooked at high temperatures, as well as in cigarette smoke and exhaust gases. These compounds are carcinogenic via a process that involves conversion of a parent compound [by cytochrome P450 enzymes (CYPs) or other oxidases) to genotoxic N-hydroxylated metabolites. These metabolites binding to DNA and form DNA adducts, after which the DNA adducts can be converted into cancer-causing mutations. This bioactivation process has been described robustly for liver, but less is known about bioactivation of HAA in extra-hepatic tissues. Therefore, Dr. Bellami and colleagues investigated the capacity of human T lymphoctyes to bioactivate HAA and form DNA adducts. Specifically, they isolated human peripheral blood mononuclear cells, induced the production of CYPs, and confirmed the induction of activated T lymphocytes. Next, they exposed the activated cells to several HAA pro-carcinogens and measured the levels of DNA adducts formed in the cells using a very sensitive method (ultraperformace liquid chromatography-electrospray ionization multistage scan mass spectrometry), which can detect as few as 3 adducts per billion DNA bases.

This study produced important new knowledge about these potential human carcinogens and their biological effects in human cells. The study demonstrated for the first time that functional CYP1 activity could be induced in PMA/Iono activated lymphocytes. Bellami et al. found that DNA adducts were formed by two HAAs [2-amino-9H-pyrido[2,3-b]indole (AαC) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), but not by another HAA, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) or the aromatic amine, 4-aminobiphenyl. Noting that DNA adducts were produced in larger quantities by AαC as compared to other HAAs, the investigators hypothesized that AαC could itself induce CYPs. Bellami et al. were able to confirm this hypothesis and demonstrate that AαC-induced CYP activation occurred through a transcriptional mechanism that also required protein synthesis.  Therefore AαC serves as an inducer of CYP enzymes, resulting in increased bioactivation of AαC and elevated DNA damage.

Overall, Dr Langouet’s team and collaborators have developed important new information that will inform the public about cancer risk associated with AαC and other HAA. Environ. Mol. Mutagen. 57:656–667, 2016. © 2016 Wiley Periodicals, Inc.

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