Genetically modifying zebrafish for detection of harmful compounds in drug candidates

July 26, 2017, Agency for Science, Technology and Research (A*STAR), Singapore

The common zebrafish is a useful proxy for testing whether drug candidates cause organ damage. Now, researchers in Singapore have created two modified types of the fish, one that glows when experiencing toxicity, and another that metabolizes drugs in a similar way to humans. Combined, these may help pharmaceutical companies develop less toxic therapeutics.

"Roche, our partner in the study, want a way to quickly identify which of their drugs may be damaging to the liver," says Tom Carney from the A*STAR Institute of Molecular and Cell Biology.

Zebrafish and humans, despite being very different species, experience toxicity from similar drugs, making them a great . Carney's team monitored the fish to identify what genes are 'switched on' when they were dosed with a range of drugs known to be damaging to liver cells, or 'hepatotoxic', and identified four common genetic sequences that produced enzymes to neutralize the drugs. "The fish are trying to clear the drugs out, and are doing so by using a detoxification process of which these genes are parts," explains Carney.

With this knowledge, the team produced a breed of modified zebrafish that expressed a fluorescent protein when these genes were switched on, creating fish that glow in response to liver-damaging drugs.

In practice, the fish could offer an easy way for to remove from their pipeline before superfluous R&D expenditure.

Despite zebrafish and humans sharing similar detoxification pathways, the detoxifying enzymes differ between the species and therefore drugs can be metabolized differently. Addressing this, the scientists produced a second line of zebrafish in which the liver was supplemented with a key human liver enzyme. The result was the first demonstration of a 'humanized' that detoxified drugs in a much more similar way to humans. This is especially important considering that metabolites can be more damaging than the originally ingested medication—as is the case with the common painkiller, paracetamol.

These models offer a promising line of inquiry into a drug testing technique that is scalable, affordable, and allows for high-throughput screening. In the future, Carney's team may combine their two models in order to create a line of that accurately metabolizes toxic medications and provides an immediate, visible signal for drugs that may harm patients.

Explore further: Multichannel EEG recordings enable precise brain wave measurement of fish

More information: Kar Lai Poon et al. Transgenic Zebrafish Reporter Lines as AlternativeIn VivoOrgan Toxicity Models, Toxicological Sciences (2016). DOI: 10.1093/toxsci/kfw250

Kar Lai Poon et al. Humanizing the zebrafish liver shifts drug metabolic profiles and improves pharmacokinetics of CYP3A4 substrates, Archives of Toxicology (2016). DOI: 10.1007/s00204-016-1789-5

Related Stories

Multichannel EEG recordings enable precise brain wave measurement of fish

July 5, 2017
A research team led by Professor Sohee Kim at the Robotics Engineering department succeeded in measuring zebrafish's multi-channel electroencephalogram (EEG) on June 12 for the first time in the world.

Model simulates biliary fluid dynamics in the liver and predicts drug-induced liver injuries

March 27, 2017
The liver is crucial for the detoxification of the human body. The exposure to toxins makes it particularly prone to drug-induced injury. Cholestasis, the impairment of bile flow, is therefore a common problem of drug development ...

Zebrafish help researchers identify promising drugs

July 25, 2012
(Medical Xpress) -- “Jaws” it isn’t, but the tiny striped zebrafish is helping Tulane University scientists take a big bite out of a tough question — what drugs might be beneficial for treating psychological ...

Toxic liver effects of fifteen drugs predicted using computational approach

February 2, 2017
A team of researchers has used a computational modeling approach to analyze and compare the toxic effects of fifteen different drugs on the liver, according to a study in PLOS Computational Biology.

Individual adverse drug responses could be predicted by a simple blood test

May 31, 2017
Severe illnesses sometimes require treatment regimens carrying grave risks, including organ failure. Now, a non-invasive technique developed at A*STAR could help predict patient vulnerability to potentially toxic drugs. 

Scientists surprised to discover lymphatic 'scavenger' brain cells

May 1, 2017
The brain has its own inbuilt processes for mopping up damaging cellular waste—and these processes may provide protection from stroke and dementia.

Recommended for you

The complicated biology of garlic

April 26, 2018
Researchers today generally agree that eating garlic, used for thousands of years to treat human disease, can reduce the risk of developing certain kinds of cancers, cardiovascular disease, and type 2 diabetes. Nevertheless, ...

CRISPR-based diagnostic SHERLOCK optimized for rapid use during viral outbreaks

April 26, 2018
In a paper published today in Science, researchers at Broad Institute of MIT and Harvard report a new tool that engineers the CRISPR-based diagnostic SHERLOCK for rapid outbreak response. The updates to SHERLOCK, which was ...

Too liberal use of oxygen increases risk of death in acutely ill adult patients

April 26, 2018
McMaster University researchers have found there is such a thing as too much oxygen for acutely ill adults.

Noninvasive brain tumor biopsy on the horizon

April 26, 2018
Taking a biopsy of a brain tumor is a complicated and invasive surgical process, but a team of researchers at Washington University in St. Louis is developing a way that allows them to detect tumor biomarkers through a simple ...

Lab-on-a-chip delivers critical immunity data for vulnerable populations

April 25, 2018
For millions of displaced people around the world—many of them refugees, living in temporary shelters under crowded conditions—an outbreak of disease is devastating. Each year, the measles virus kills more than 134,000 ...

Want new medicines? You need fundamental research

April 25, 2018
Would we be wise to prioritize "shovel-ready" science over curiosity-driven, fundamental research programs? Would that set the stage for the discovery of more new medicines over the long term?

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.