ReviewIdiosyncratic toxicity: the role of toxicophores and bioactivation
Section snippets
The problem – reactive metabolites?
It is generally thought that reactive, electrophilic compounds, formed either from the parent drug (e.g. a reactive quinoneimine from paracetamol) or as a consequence of increased cellular production of reactive oxygen and/or nitrogen species (hydroxyl radical, superoxide and peroxynitrite) are responsible for initiating toxicity. Reactive metabolites can cause tissue damage by direct modification of cellular proteins, such as covalent binding of the drug to the protein, or oxidation of
The solution?
The first alert to potential toxicity should be the identification of potential toxicophores within the proposed candidate compound, by the medicinal chemist or the drug metabolist. Although this is not a sufficient reason for stopping drug development at this stage, it should serve as a warning. Obviously, prevention of the release of potentially toxic drugs on the market takes a high priority. However, with the growing use and stringency of toxicity screens, there is an increased chance of
Detection of cell stress
Further knowledge of the molecular consequences of drug bioactivation, downstream from glutathione depletion and covalent binding, are required to ultimately define a drug and/or particular dose as toxic or non-toxic. Downstream molecular pathways, such as transcription factor activation, gene and protein expression, and protein degradation, will give greater insight into the underlying mechanisms of toxicity. Transcription factors (proteins involved in cellular signalling and modulation of
Transcription factor regulation
The transcription factor nuclear factor erythroid-2 related factor (Nrf2) is currently the subject of intense investigation into chemotherapy and drug toxicity. Nrf2 nuclear localization has been shown to result in the expression of numerous defensive genes, such as NAD(P)H:quinone oxidoreducatse-1 (NQO1) and heat shock proteins (HSPs) [52]. It has also been confirmed that Nrf2 associates with a novel cytoplasmic protein, Kelch-like ECH-associated protein1 (Keap1), that directly negatively
Downstream considerations
The majority of idiosyncratic drug reactions (IDRs) at initial challenge, require weeks, if not months, of chronic dosing, before they are apparent 21., 64.. This is suggestive of an accumulation or chronic depletion mechanism. For example, accumulation of a drug–protein conjugate might eventually initiate a toxic or immune reaction when the concentration of conjugate reaches a specific level. Conversely, chronic low-level reactive metabolite formation could lead to lowered antioxidant levels
Acknowledgements
We would like to thank Pfizer and the Wellcome Trust.
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