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Enzyme, drug discovery at Scripps Research may help smokers quit

Ever wondered why it’s so hard to quit smoking? It may not be due to social pressure, lack of will power or advertising after all. Much of the difficulty may be caused by a microscopic enzyme known as CYP2A6.

Scientists at The Scripps Research Institute have just published their findings on a drug called methoxsalen, and its interaction with CYP2A6. Their findings could reduce tobacco-related cancer and help smokers quit.

CYP2A6 belongs to a family of drug-metabolizing enzymes known as cytochromes P450, which are found in the human liver. Jason Yano, the lead author of the institute’s published findings, explained that although CYP2A6 is not considered a major player in overall drug metabolism, it is the principal enzyme in the breakdown of nicotine in the body.

“It’s CYP2A6’s ability to rapidly degrade nicotine that causes smokers to continue smoking to replenish their nicotine levels,” Yano said, who researched the enzyme as a postdoctoral fellow in the institute lab led by Eric Johnson. Since methoxsalen keeps CYP2A6 from breaking down nicotine in the body, this increased nicotine presence leads to fewer nicotine cravings.

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In addition to breaking down nicotine, CYP2A6 also activates tobacco-specific pro-carcinogens. Left inactive, these pro-carcinogens may never become harmful.

“Without the enzyme, the body can get rid of the carcinogens in other ways,” Yano said. Therefore, inhibiting CYP2A6’s activation of these carcinogens may reduce smoking-related cancers.

Non-smokers may benefit from increased understanding of drug metabolism as well.

“To figure out how to get away from drug metabolism,” said Yano, “that’s particularly important for keeping precious compounds in the blood.” He used the example of slowing the metabolism of drugs treating AIDS to keep them in the body longer.

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However, methoxsalen does have its drawbacks. It is currently used as a prescription drug to treat psoriasis, vitiligo and a type of lymphoma known as mycosis fungoides. It falls into a class of drugs called psoralens and can be found under the brand names Oxsoralen, Oxsoralen-Ultra, Uvadex, 8-MOP and Ultra MOP.

Patients taking methoxsalen can experience a range of side effects including skin cancer and sensitivity to light. They must also avoid foods such as carrots, limes and mustard, with which the drug may react. Besides these side effects, Yano said methoxsalen can also inhibit other drug-metabolizing enzymes, possibly causing dangerous drug interactions.

The goal of Yano and his colleagues’ research was to understand how inhibitors such as methoxsalen work, in the hope that more specific inhibitors with less side effects can be designed.

“This provides a very clear picture of how methoxsalen interacts with the enzyme and provides a picture of the fit between the inhibitor and the enzyme,” said Eric Johnson, supervisor of Yano’s project.

“Now we are in a position to find other chemicals that can fit into the active site to block its ability to degrade nicotine and activate the tobacco-related carcinogens,” Yano said.

The current research is based on a trail of work that stretches all the way to Japan. Tetsuya Kamataki and his colleagues at Japan’s Hokkaido University studied the presence of CYP2A6 in the Japanese population, finding that a significant percent of the population lacked the enzyme.

“He found that people who harbored these genetic defects were less likely to become smokers and had a statistically significant reduction in tobacco-related cancers if they were smokers,” Yano said.

The story then moved to Canada, where Rachel Tyndale and Edward Sellers of the University of Toronto attempted to mimic the genetic defects found by Kamataki.

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Tyndale and her colleagues administered methoxsalen in combination with an oral dose of nicotine.

“They found that methoxsalen could inhibit nicotine metabolism in vivo, and that smokers who were given methoxsalen and the oral dosage of nicotine wanted to smoke less,” Yano said.

These findings led to The Scripps Research Institute’s investigation of how methoxsalen inhibits enzyme activity.

Yano’s research was funded through grants from the Tobacco-Related Disease Research Program and the National Institute of Health. It was conducted over two years, ending on June 30 of this year.

Besides funding, the research of Yano and his colleagues also required cooperation.

“It’s a good example of the collaboration that goes on at Scripps,” David Stout said. Stout collaborated on the project as a crystallographer. “Most projects require labs to work together. It’s often a team effort.”

Crystallography is a technique widely used to determine atomic structure, in which an X-ray beam at a single wavelength is passed through a crystal.

“The crystal defracts the X-rays, which gives you information about the arrangement of the atoms inside the crystal,” Stout said. Through computing and mathematics, these defraction patterns can be reconstructed into an image of the molecules.

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Not only did Johnson and Stout’s labs join forces within The Scripps Research Institute, but Yano and his colleagues also teamed up with other institutions. Data for the project was collected at the Stanford Synchrotron Radiation Laboratory.

The result was a clearer-than-ever picture of how enzyme-inhibiting drugs interact with cytochromes P450 in the liver.

Yano and his colleagues also studied another enzyme known as 3A4, the principle P450 player in drug metabolism. This single enzyme is responsible for 50 percent of all drug metabolism, Yano said.

Stout called 3A4 “the most promiscuous” enzyme because of its ability to oxidize a wide variety of drugs.

Stout said that CYP2A6 is only one of a series of P450s being researched at the institute. The enzyme family includes 60 enzymes, each of which is specialized to interact with different compounds in the body.

“Our goal is to look at all of the drug-metabolizing human P450s,” Stout said.

Though Johnson doesn’t know of any current clinical studies of the use of methoxsalen to help smokers quit, Yano mentioned that several pharmaceutical firms, including Nicogen, are working to design similar inhibitors.