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Prestigious NIH award fuels research on human clearance of drugs, foreign chemicals

Friday, October 30, 2015

LAWRENCE — Emily Scott, professor of medicinal chemistry at the University of Kansas, has been recognized with a MERIT Award from the National Institutes of Health’s National Institute of General Medical Sciences. It’s a rare and important recognition — researchers can receive them only once in a career. 

Scott’s research focuses on a large family of proteins called “cytochrome P450s” that are embedded in cell membranes, where they perform the first and most critical step in removing foreign chemicals from the body.

“Every day, we’re exposed to these chemicals in the forms of the medicines we use to keep and make us well, the cleaning products we use at home, pesticide residue and additives in foods we eat, and pollutants in the air we breathe,” Scott said.

But many of these foreign chemicals tend to dissolve in the membranes of our cells where they are difficult to remove, she said.

“Understanding how quickly P450s remove drugs from our body allows physicians to determine how frequently medicines should be given — and which medicines should not be taken in combination,” Scott said. “Understanding which P450s remove or activate toxins that can cause DNA damage and cancer helps us determine how to prevent diseases. Understanding how individual P450 enzymes make undesirable amounts of normal hormones helps us shut down breast and prostate cancers.”

Scott said scientists have struggled to figure out which member of the P450 family deals with each different foreign chemical and to know enough about that individual P450 to manipulate just the one and not the other related P450s.

Her work on the enzymes earned Scott exceptionally early recognition from the NIGMS, as she started her research career only 11 years ago. NIGMS selection for the MERIT Awards acknowledges scientists who have made highly valuable contributions over at least 10 years of previous NIGMS-funded research — and who are judged likely to continue to do so. In today’s competitive funding climate, the MERIT Award, which converts grants from a typical four-year funding period to up to 10 years of NIH funding, is highly prized for its ability to support sustained focus on creative, innovative research.

To help distinguish between P450 family members, the Scott Lab uses the equivalent of a P450 “family photo album.” Scott said by taking images of individual P450 proteins at the atomic level using a process called “X-ray diffraction,” they can tell the P450 enzymes apart “just like you can tell the difference between Grandma Dorothy and Uncle Thomas in the family album.”

“By taking enough snapshots of both family members going about their daily activities, you could surmise that blocking access to the kitchen would significantly impair Grandma Dorothy’s ability to make her famous cherry pie without adversely affecting Uncle Thomas, who is allergic to cherries,” she said. “Similarly, multiple snapshots of a particular P450 going about its various functions allows scientists to identify ways to stop — or facilitate — the function of one P450 without affecting the others.”

With the most recent grant, the Scott Lab will focus on P450 enzymes that are involved in a range of diseases, including lung cancer and colon cancer, with the goal of providing information to develop more effective drugs.

“A further complication addressed in this new grant is that P450 family members don’t work alone,” Scott said. “Just like Grandma Dorothy has her groceries delivered to the house to be able to make her special cherry pie, P450s need electrons delivered by helper proteins — called NADPH-cytochrome P450 reductase and cytochrome b5 — to perform their functions. Unfortunately, scientists don’t currently have any good snapshots of how this happens. The problem is that the interactions between the proteins are transient — that is, the handoff between the grocery delivery guy and Grandma Dorothy — doesn’t last long enough, and the result is a blurry photo.”

To get a clear image of electron delivery to P450s, the Scott Lab is figuring out how to slow down and stabilize the interaction between P450 and its helper proteins and how to use different techniques equivalent to using different types of cameras.

Such information will help scientists in the Scott lab and their collaborators figure out, for example, how to use a P450 found only in colon cancer cells to kill just these cells. But there are many other applications for this basic science. Understanding how individual P450 family members deal with different drugs, toxins and other foreign chemicals — and how helper proteins facilitate this process — will improve the drugs in clinical use for myriad diseases. The work will help researchers to understand how cancers start and design new drugs to treat cancer and many other human diseases.

“And that will keep Grandma Dorothy in the kitchen making her famous cherry pie for many more years to come,” Scott said.


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