131Increasingly, genetic polymorphisms of transporter and receptor systems are also
recognized as causing interindividual variation in drug response and drug toxicity.
However, pharmacogenetic and toxicogenetic factors rarely act alone; they produce
a phenotype in concert with other variant genes and with environmental factors.
Environmental factors may affect gene expression in many ways. For instance,
numerous drugs induce their own and the metabolism of other xenobiotics by inter-
acting with nuclear receptors such as AhR, PPAR, PXR and CAR. Genomics is
providing the information and technology to analyze these complex situations to
obtain individual genotypic and gene expression information to assess the risk of
toxicity.
Biomarkers of Drug Toxicity
This topic is discussed in detail in a special report on biomarkers (Jain 2015 ).
Clinical chemistry endpoints for routine animal toxicity testing and clinical trial
safety monitoring have been used for over 25 years. Drug-induced damage to the
liver is the most common type of toxicity that results in withdrawn of a drug from
clinical trials or from further marketing. Similarly, cardiotoxicity is a frequent
occurrence in patients undergoing cancer chemotherapy. However, the currently
available biomarkers for these common types of drug-induced toxicities have lim-
ited sensitivity or predictive value. The proteomic tools available today are enabling
us to tap into the wealth of genome sequence information to discover and carefully
investigate associations of thousands of proteins with drug-induced toxicities.
Methods for earlier, more accurate prediction and detection of toxicity can save
lives by increasing the window for successful medical treatment, while identifying
the best treatment methods for each patient.
Drug-Induced Mitochondrial Toxicity
Mitochondria are recognized as the producers of the majority of energy cells need
for their normal activity. Because drugs can produce toxic effects through damaging
mitochondrial bioenergetics, use of the organelle can be an effective and reliable
bio-sensor to predict drug safety. Classic methods used to test the toxicity of a wide
range of compounds on isolated mitochondrial fractions were later replaced by
novel high-throughput methods to investigate the safety of a very large number of
new molecules. The assessment of “mitochondrial safety” for new discovered mol-
ecules is of interest for pharmaceutical companies, which can now select com-
pounds lacking mitochondrial toxicity for further trials, thus avoiding the possibility
of discontinuation of clinical trials later on due to mitochondrial toxicity (Pereira
et al. 2009 ).
Many drugs used to treat these diseases can cause toxic side effects that are often
due to inhibition of mitochondrial function. MitoSciences’ MitoTox line of assays
can identify drug toxicity before symptoms start to appear. Tests under development
Role of Pharmacogenetics in Pharmaceutical Industry