Environmental Factor, March 2005, National Institute of Environmental Health Sciences
New "Chip" Technology for High-Throughput Toxicity Analyses
By Jerry Phelps
Advance: NIEHS-supported researchers at the University of California, Berkeley and Rensselaer Polytechnic Institute have created a new method that mimics liver metabolism allowing rapid testing of potential drugs. The technology employs P450 enzymes on a glass slide or "chip" and can be used to identify compounds that would be activated by the liver and to "weed out" those that have toxic metabolites. Using the new system, the metabolites produced were applied to human breast cancer cells. The researchers were able to demonstrate that the new technique accurately mimics the activation of the cancer agents Cytoxan (cyclophosphamide) and Tegafur along with producing the toxic metabolites of acetaminophen. This research was supported by the Small Business Technology Transfer Program.
This new technology, dubbed the "MetaChip," could provide a "high-throughput microscale" method for rapid testing of a variety of potential drugs and their P450-derived metabolites. The research team plans to expand the technology for use with other cell types, compounds, and enzymes involved in drug metabolism. Ultimately, this technique could lead to elimination of toxic drug candidates much earlier in the discovery process allowing researchers to focus their efforts on more promising, less toxic alternatives.
Screening for toxicity of potential new drugs presents a bottleneck in the drug discovery process. New technologies have led to a dramatic increase in the number of compounds that have pharmacologic potential, but the slowness of toxicity screening prevents many compounds from ever being tested and therefore slows the process of discovery and bringing new drugs to market. Often, researchers must select drug candidates for studies based on limited information. There is a lack of rapid, in vitro testing methods that can mimic human metabolism and test for cell-specific toxicity of these potential drugs and, just as importantly, their metabolites.
The liver is the primary site of metabolism of the vast number and types of chemicals that humans are exposed to on a daily basis. The most important class of metabolic enzymes in the liver is the cytochrome P450s, which are actively involved in the clearance of drugs. The P450s start the process of breaking down chemicals so they can be excreted, but during metabolism, some active metabolites, which have the desired pharmacologic effects, can be created. The converse is also true; metabolism can produce toxic metabolites, such as in the breakdown of the common analgesic acetaminophen.
The discovery was published in the Proceedings of the National Academy of Sciences, January issue.