Title:The Role of Metabolism in Toxicity of Polycyclic Aromatic Hydrocarbons and their Non-genotoxic Modes of Action
Volume: 22
Issue: 8
Author(s): Jan Vondráček*Miroslav Machala*
Affiliation:
- Institute of Biophysics of the Czech Academy of Sciences, Brno,Czech Republic
- Veterinary Research Institute, Brno,Czech Republic
Keywords:
Benzo[a]pyrene, DNA damage, oxidative stress, cell survival, cell proliferation, cell-to-cell communication, AhR, PAH
metabolism.
Abstract: Polycyclic aromatic hydrocarbons (PAHs) represent a class of widely distributed environmental pollutants
that have been primarily studied as genotoxic compounds. Their mutagenicity/genotoxicity largely depends
on their oxidative metabolism leading to the production of dihydrodiol epoxide metabolites, as well as additional
metabolites contributing to oxidative DNA damage, such as PAH quinones. However, both parental
PAHs and their metabolites, including PAH quinones or hydroxylated PAHs, have been shown to produce various
types of non-genotoxic effects. These include e.g., activation of the aryl hydrocarbon receptor and/or additional
nuclear receptors, activation of membrane receptors, including tyrosine kinases and G-protein coupled receptors,
or activation of intracellular signaling pathways, such as mitogen-activated protein kinases, Akt kinase
and Ca2+-dependent signaling. These pathways may, together with the cellular DNA damage responses, modulate
cell proliferation, cell survival or cell-to-cell communication, thus contributing to the known carcinogenic
effects of PAHs. In the present review, we summarize some of the known non-genotoxic effects of PAHs, focusing
primarily on those that have also been shown to be modulated by PAH metabolites. Despite the limitations
of the available data, it seems evident that more attention should be paid to the discrimination between the
potential non-genotoxic effects of parental PAHs and those of their metabolites. This may provide further insight
into the mechanisms of toxicity of this large and diverse group of environmental pollutants.
