Toxicology, Cellular Stress & Stress Response

The understanding of drug–body interactions is crucial to drug development. Drug absorption, distribution, metabolism and excretion (ADME) is critical in all phases of drug development programs, providing key insights into how a drug will ultimately be treated or accepted by the body. In the late 1980s to the mid-1990s, 40% of all drug failures in clinical trials were due to unfavorable toxicology and ADME profiles. By developing and using new focused genomic tools, researchers are better prepared to test compounds to protect human health and the environment. 

Several hundred key genes in at least 13 different biological pathways can be activated in response to toxic drugs. Profiling the expression of these genes in human cell lines (such as hepatocytes) or organs (especially livers) of mice or rats treated with candidate drugs can help indicate which toxicological responses have been induced. Understanding these mechanisms can then guide chemical modifications to avoid the observed toxic responses rather than completely dismissing a drug class otherwise effective at preventing or treating the target disease phenotype. The toxic response pathways can be independent or interrelated. For example, inhibition of β-oxidation leads to steatosis, and uncoupling mitochondrial energy metabolism leads to apoptosis and necrosis. Drugs affecting reactive oxygen species metabolism or cellular redox status cause oxidative stress and induce antioxidant responses. These and other reactive drugs also directly damage DNA or inhibit its repair, thereby activating DNA damage signaling and DNA repair pathways. More extreme conditions of prolonged exposure or excess damage to DNA, cells or tissues may induce apoptosis and necrosis. Interference with protein synthesis causes endoplasmic reticulum stress and activates the unfolded protein response, resulting in up-regulation of heat shock protein and chaperone gene expression. Increased expression of the cytochrome P450 and other phase I drug metabolism enzymes occurs when drugs inhibit or overwhelm their chemical modification activities. More severe and complex phenomena result when drugs inhibit fatty acid and lipid metabolism (β-oxidation), including the lipid storage disorders of steatosis, cholestasis and phospholipidosis. Toxic responses to drugs in immune system cells bring about immunotoxicity and immunosuppression.