Microarray scan image shows the complete reaction system in the sol-gels resulting in vivid cytotoxicity (as shown by distinct spots of either red or light yellowish-green color on the stained array).

In recent advances, large numbers of promising compounds for potential new drugs have been identified. Yet, the biggest obstacle that remains in drug discovery is the lack of a reliable way to screen these drug candidates to determine toxicity levels early enough in the process.

To tackle the problem, researchers at Rensselaer and the University of California at Berkeley have developed the MetaChip (metabolizing enzyme toxicology assay chip), a biochip that mimics the metabolic reactions in the human liver, allowing for rapid and far more effective screening for compound toxicity.

“The concept of the MetaChip is to make sure we eliminate bad compounds early enough so they don’t make it all the way through the process, get approved, and then have to get recalled, such as we’ve seen in the case of Vioxx,” says Jonathan Dordick, the Howard P. Isermann ’42 Professor of Chemical and Biological Engineering at Rensselaer.

To help market the chip, researchers received a National Institutes of Health grant for nearly $500,000 and started a biotech company, Solidus Biosciences.

The liver plays a central role in the detoxification of drugs. Through the process of metabolism, liver enzymes break down, neutralize, and excrete foreign chemicals that enter the body through foods and pharmaceuticals.

In most cases, the metabolized chemicals, called metabolites, are innocuous. In other cases, they are beneficial. Some metabolites, however, are toxic, and this toxicity is often difficult to predict and screen for at early stages of the drug-discovery process.

The MetaChip, for the first time, enables the initial and high-throughput analysis of metabolism-induced toxicology to be performed, Dordick says.

“The metabolized drug candidates can be produced and screened against human cell lines for the first time on a single microscale platform,” Dordick says. “We can see firsthand how certain compounds are metabolized through these enzymes. We can then rapidly test the compound’s activated components for toxicity levels on potentially any type of cell to determine organ-specific drug toxicity.”

The MetaChip contains P450 enzymes (the liver’s main detoxification enzymes) encapsulated in a sol-gel, a glasslike material that immobilizes the enzymes on a typical microscope slide so that thousands of drug candidates can be tested for toxicity simultaneously on a single slide.

To market the MetaChip, Dordick and Berkeley colleague Douglas Clark plan to develop a more user-friendly, bench-top system. Such a device would allow researchers to slide a MetaChip into an automated machine equipped to hold typical cell-screening devices so that drug components can be tested on different cells.

Published April 1, 2005