Role Of Metabolism In Toxicity Research Articles

The Role of Metabolism in Toxicity of Polycyclic Aromatic Hydrocarbons and their Non-genotoxic Modes of Action

The Role of Metabolism in Toxicity of Polycyclic Aromatic Hydrocarbons and their Non-genotoxic Modes of Action

The Role of Metabolism in Toxicity of Polycyclic Aromatic Hydrocarbons and their Non-genotoxic Modes of Action.

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.

Predictive Value of Liver Slices for Metabolism and Toxicity in Vivo: Use of Acetaminophen as a Model Hepatotoxicant

To establish the usefulness of liver slices as predictive models for in vivo metabolism and toxicity, acetaminophen was used as a model hepatotoxicant for which the role of metabolism in toxicity is well documented. Acetaminophen was incubated with liver slices prepared from the rat and hamster since these species differ in susceptibility to acetaminophen-induced hepatotoxicity. Formation of acetaminophen metabolites (sulfate, glucuronide, and glutathione conjugate), slice glutathione levels, and slice histopathology were assessed. Acetaminophen (0.5, 1, and 2 mM) induced a dose-dependent depletion of glutathione in hamster slices (sensitive species) but not rat slices (insensitive species). Formation of the acetaminophen toxic metabolite, as measured by glutathione conjugate formation, was much lower in rat slices compared with hamster slices. Rat slices also showed greater activity of the nontoxic sulfation and glucuronidation pathways. These data predicted an 11-fold greater susceptibility to toxicity in the hamster based on the proportion of the dose metabolized to the reactive species. In vivo data, using hepatic glutathione depletion as an indicator of toxic metabolite formation, would predict a similar difference (13.3-fold) between the hamster and the rat. To ascertain if the characteristic centrilobular lesion induced by acetaminophen in vivo could be reproduced in vitro, liver slice histopathology was assessed 6 and 12 hr after a 2-hr treatment with acetaminophen (2 mM). Discrete damage to the centrilobular regions of the liver were noted in hamster but not rat slices. Overall, based on metabolite formation, glutathione depletion, and slice histopathology, the liver slices were excellent predictors of acetaminophen hepatotoxicity in vivo.