Testing times for microscopic liver mimics

2019-02-28 07:01:00

By Paul Rodgers A MENAGERIE of genetically engineered microorganisms is being developed to mimic the way the human liver reacts to potential new drugs. British scientists are working on the project for pharmaceuticals giant Glaxo. “We’re trying to predict what will happen with drugs in people,” says Mike Tarbit, head of drug metabolism at Glaxo’s research and development centre at Ware in Hertfordshire. Some potential drugs look promising but may not be able to withstand the body’s natural defences long enough to do much good before they are broken down. Some of the compounds that result from their breakdown can also lead to unpredictable side effects. The liver is the main organ involved in processing and getting rid of drugs. Drugs that are taken orally are carried in the bloodstream straight to the liver where, in some cases, as much as 90 per cent of the dose is immediately broken down, according to Barry Ross, the Glaxo group’s research director. Even if drugs are injected, they only have around three minutes to circulate before they reach the liver. But more of an injected dose tends to survive its encounter with the liver because the drug is more diluted by the time it gets there. The main culprits are a family of enzymes produced in the liver called cytochrome P-450s. Their main function is to act as catalysts, promoting chemical reactions that add hydroxyl groups to vulnerable parts of foreign molecules, including drugs. Some of the enzymes also tackle the invading molecules by cutting them into fragments. The resulting molecules are usually more soluble in water than fat and so can be easily excreted, either via the bile duct or the kidneys. People typically have a dozen different P-450s in their livers, and Tarbit’s team has so far successfully transferred the genes for manufacturing nine of them – three into yeast cells, Saccharomyces cerevisiae, and six into Escherichia coli bacteria. The project was complicated by the need to limit the production of the enzymes. If the microorganisms produce too much, the enzymes clot to form useless lumps of protein. The scientists also had to include the genetic code for another enzyme, called reductase, which helps the P-450s to work. Cultures of the genetically engineered bacteria and yeast are fed on samples of potential new drugs. Their waste products are then tested to determine what molecules the enzymes have produced and how fast they work. The information allows Glaxo’s chemists to tweak their drugs to make them less susceptible to enzyme attack. And because it gives pharmacologists an extra test for toxicity and other possible side effects,