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  • Review Article
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Elucidating mechanisms of drug-induced toxicity

Key Points

  • A major cause of attrition in the drug development pipeline is the toxicity of drugs, which is still difficult to predict early in drug discovery.

  • Many toxicities result from the metabolic activation of compounds to reactive intermediates that can then covalently bind to cell macromolecules, such as proteins and DNA. This covalent binding can perturb cell-signalling events or generate DNA adducts that might lead to mutations.

  • Major drug toxicities can be grouped into four categories on the basis of their underlying mechanism: hypersensitivity and related immunological reactions; off-target pharmacology; biological activation to toxic metabolites; and idiosyncratic toxicities. Biological activation and covalent bonding are particularly significant because they contribute in many cases of toxicities in different categories. The most difficult to predict toxicities are rare or 'idiosyncratic' toxicities and drug–drug interactions.

  • Recent advances in genomics, proteomics and metabonomics should positively aid the prediction of toxicity by enabling more accurate studies of genetic variation, such as polymorphisms in drug-metabolizing enzymes, and by further elucidating the pathways involved in drug-mediated cell toxicity.

  • An important aspect of proteomics in drug toxicity is to shed light on which proteins are targets for covalent binding by drugs and how this affects protein networks on a larger scale. 'Sensors' for toxicity have already been used with some success, particularly proteins that are involved in phase II metabolism and antioxidants such as glutathione.

  • There is still much progress to be made in defining targets for toxicity, identifying and validating biomarkers for predicting adverse reactions, and improving current toxicological models. This progress will rely on interactive and reiterative collaborations between academic and industrial researchers and drug safety experts.

Abstract

The early and high-throughput application of assays for non-genetic toxicity is of great interest to the pharmaceutical industry, although few systems have been validated as being of good predictive value. New technologies could enable toxicity to be studied in the context of systems biology. An important factor to be considered is the metabolism of drugs to reactive intermediates. Chemical reactions of these with cell and tissue nucleophiles are relatively well understood, but predicting how biological modifications will affect signalling and regulatory networks remains a challenge. Some of these pathways could be useful as sentinels for toxicity. This article will cover some examples of drug toxicity and the prospects for future technology development.

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Figure 1: Some events associated with the toxicity of drugs and xenobiotics.
Figure 2: Use of bacterial SOS assay to identify genotoxins with the umu response.
Figure 3: Identification of proteins modified by reactive drug metabolites.
Figure 4: The KEAP1/NRF2/ARE system involved in transduction of chemical signals.

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Acknowledgements

The authors acknowledge support from a number of US Public Health Service Grants.

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Correspondence to F. Peter Guengerich.

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DATABASES

Entrez Gene

ASK1

COX2

CYP2C9

CYP3A4

JNK1

KEAP1

UDP-glycosyltransferase 1A1

Glossary

METABOLISM

In this review, the term is mostly restricted to molecular changes that drugs undergo but can also refer to individual transformation reactions, as well as overall processes.

COVALENT-BINDING

Formation of a chemical bond between a drug or its metabolite (electrophile) with a cellular nucleophile (generally protein, RNA or DNA).

ON-TARGET TOXICITY

Toxicity that occurs because of modulation of the primary pharmacological target (for example, receptor or enzyme), whether in the same cell tissue or not.

OFF-TARGET PHARMACOLOGY

Adverse effects resulting from interaction of a drug with targets other than intended therapeutic targets.

BIOLOGICAL ACTIVATION

The biological transformation of a drug to toxic metabolites, which often results in organ- and tissue-specific toxicity.

IDIOSYNCRATIC TOXICITIES

Rare toxicities that are thought to represent unique susceptibility of affected individuals.

DISPOSITION

The transport of a drug and its metabolites in biological and physical processes, apart from metabolism.

TRANSCRIPTOMICS

Large-scale studies of the expression of genes at the mRNA level, typically with microarray technology.

SYSTEMS BIOLOGY

The use of mathematical models to study how multicomponent systems function and react to external perturbation and stress.

INTERACTOME NETWORKS

Groups of genes and proteins whose interaction results in functions or functional changes, such as those gene–protein groupings that are coordinately regulated by toxic insult.

METABONOMICS

Large-scale analysis of changes in the composition of metabolites of intermediary metabolic pathways, usually done by ex vivo analysis of biofluids by NMR and mass spectrometry.

SENSOR TRIGGERS

Proteins whose modification by oxidants and electrophiles triggers activation of a cellular response. Candidate sensor-trigger proteins typically have reactive cysteine thiol groups.

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Liebler, D., Guengerich, F. Elucidating mechanisms of drug-induced toxicity. Nat Rev Drug Discov 4, 410–420 (2005). https://doi.org/10.1038/nrd1720

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