Genomics and Drug Toxicity

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Science  22 Oct 2004:
Vol. 306, Issue 5696, pp. 575
DOI: 10.1126/science.1105854

As genomics has revolutionized the study of biology, so has it affected how drugs are discovered. Pharmaceutical companies have also realized another major application: how drugs are assessed for safety. The analysis of gene expression profiles is now actively used alongside conventional toxicological assays to assess drug safety. Such toxicogenomic analysis is being used to predict drug toxicities and to gain a more in-depth understanding of toxic mechanisms, so that more successful drug candidates can be selected.

The U.S. Food and Drug Adminstration (FDA) sees genomics as a beneficial aid to the drug risk assessment process primarily through its ability to identify specific patients who are either likely to benefit from a particular drug or who may experience harm. The use of toxicogenomics also has promise in proving hypotheses that support safe drug use in humans through a mechanistic understanding of toxicities found in drug-treated animals. Take the case in which rats were treated with a certain class of hypolipidemic drugs. Changes in the expression of specific liver genes were seen that have been shown to correlate with observed liver toxicity. However, when treated human and rat liver cells were compared, analogous gene expression changes were not seen in the human cells.* Thus, by gaining a better idea of the mechanisms of toxicity in an animal species, it becomes feasible to examine species-specific effects to better assess the possible relevance of animal findings to humans. After a number of conferences and workshops based on recent FDA draft guidelines, there was agreement that some standards ought to be adopted for the generation and subsequent submission of toxicogenomic data to the FDA. This would help ensure that any regulatory decisions based on an interpretation of data can be made in a consistent manner.


A number of groups are actively addressing the issues of standardization of toxicogenomic data generation and exchange. The European Bioinformatics Institute (EBI) has created Tox-MIAMExpress to incorporate toxicity and toxicogenomics data into their Array Express database. Such efforts help identify the essential elements of a microarray experiment that are critical to interpreting a gene expression profile in the context of an associated toxicity. Some aspects of toxicogenomics experiments that are suitable for further standardization include data normalization methods, statistical assessments of gene expression, gene annotation and function, data visualization methods, and issues related to quality control of transcripts and probes.

Once a compound is selected for development by a pharmaceutical company, submission of toxicogenomic data to the FDA as part of a risk assessment package may be needed to help address safety concerns. An approach being taken by the Clinical Data Interchange Standards Consortium (CDISC) Pharmacogenomic Standards nonclinical working group is to develop hypothetical cases in which the submission of toxicogenomic data would assist in the interpretation and determination of the relevance of specific toxicity issues. In the example of the hypolipidemic drugs mentioned above, the availability of toxicogenomic data submission standards would offer drug companies the ability to submit data at a molecular level highlighting the species-specific nature of an animal finding, thereby helping to address the safety concerns of regulators.

The development of standards for toxicogenomic data generation and interpretation will help establish toxicogenomic approaches as scientifically accepted practices in the complex process of drug risk assessment. Central to this process is the continuation of the ongoing dialogue between molecular and traditional toxicologists from drug companies, regulatory bodies, and academia. The development of a scientific consensus on toxicogenomic data standards and data interpretation would mean fewer safety concerns and fewer delays in the drug approval process, resulting in improved availability of safe and effective drugs. The development and acceptance of toxicogenomic data submission standards promise to significantly improve the drug risk assessment process, which would benefit the pharmaceutical industry and public alike.

Peter G. Lord is in Pharmaceutical Research and Development at Johnson & Johnson in Raritan, NJ. Thomas Papoian is at the U.S. Food and Drug Administration in Rockville, MD.

  • *J. W. Lawrence et al., J. Biol. Chem. 276, 31521 (2001).

  • †W. B. Mattes et al., Environ. Health Perspect. 112, 495 (2004).

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