Biomarcadores de toxicidad

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Toxicology 245 (2008) 175–181

Genomic and genetic biomarkers of toxicity
Donna L. Mendrick ∗
Department of Toxicogenomics, 50 West Watkins Mill Road, Gaithersburg, MD 20878, United States Received 1 October 2007; accepted 20 November 2007 Available online 28 November 2007

Abstract Biomarkers in general use today are diagnostic in that theyreflect an organ’s ongoing dysfunction or damage. Unfortunately, in some cases the change in the biomarker occurs too late for effective medical intervention such as seen with acute renal failure. New biomarkers of toxicity are needed to (a) alert physicians of subtle changes prior to organ dysfunction or damage to enable preventive measures and (b) predict, prior to human exposure, if a drug is likelyto induce toxicity in many patients or in specific individuals. Microarray technologies can move biomarker discovery forward at an unforeseen speed as tens of thousands of genes and genetic variants can be monitored simultaneously in one biological specimen. Pharmacogenomics, herein defined as the study of a drug’s effect on gene expression, can be used to discover biomarkers in solid tissues orperipheral blood cells that are altered in animals or individuals following drug exposure. Pharmacogenetics, herein defined as the study of genetic factors that affect drug response, can be employed to identify individuals whose genetic make-up suggests they would respond poorly to a particular drug. Biomarkers discovered with these approaches can result in genomic/genetic tests, protein assays orother analytical tests. Examples of such are provided with a discussion of the unresolved issues that inhibit the use of toxicity biomarkers such as biomarker validation, reimbursement of clinical tests and patient privacy. © 2007 Elsevier Ireland Ltd. All rights reserved.
Keywords: Biomarker; Toxicogenomics; Microarray; Translational; Pharmacogenomics; Pharmacogenetics

1. Introduction Newbiomarkers are needed to (a) provide additional tools for the clinical management of patients and (b) identify unsafe drugs earlier in development. The “do no wrong” tenet of medical practice seems to be out of date as the number of drug-induced serious adverse events (ADEs) continues to rise. A recent review examined all serious ADEs reported to the US Food and Drug Administration from 1998 to 2005(Moore et al., 2007). ADEs increased 2.6-fold over

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Tel.: +1 240 364 7633; fax: +1 240 364 7602. E-mail address: dmendrick@genelogic.com.

that period with deaths growing at 2.7-fold (Fig. 1), a rate 4 times greater than the rise in prescriptions written during the same period. As has been widely reported, the submissions of new drugs and biologics to the FDA are declining despite more moneybeing spent by pharmaceutical companies (FDA, 2004). To investigate the reasons for this poor success rate, researchers at F. Hoffman-La Roche examined failures across the drug development pipeline and found that clinical safety and animal toxicology were important catalysts (Suter et al., 2004). Failures due to safety (human and animal) as compared to efficacy are shown in Fig. 2. Of drugsterminated at the time of registration when financial implications of failures are the greatest, 30% were due to clinical safety concerns com-

0300-483X/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.tox.2007.11.013

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D.L. Mendrick / Toxicology 245 (2008) 175–181

2. Biomarker panels Although a sole biomarker is appealing as it can be easier tounderstand, there are few examples in preclinical testing or in clinical practice wherein a single measurement is considered definitive. Multiple markers are required to capture the biological heterogeneity of organs involved, individual variations and disease or toxicity processes. As noted above, the technology underlying pharmacogenomics and pharmacogenetics enables assessment of thousands of genes...