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A Nicotine By-Product Reacts with Proteins, Say Scientists at The Scripps Research Institute

La Jolla, CA. October 28, 2002 - Two researchers at The Scripps Research Institute (TSRI) have discovered that a chemical called nornicotine - which is naturally present in tobacco and is also produced as a metabolite of nicotine - may contribute to the pathology of diabetes, cancer, aging, and Alzheimer's disease.

In an article to be published in the Proceedings of the National Academy of Sciences, the researchers have uncovered a previously unrecognized chemical process through which nornicotine reacts with the body's proteins.

"Nornicotine permanently and irreversibly modifies proteins, which can affect their overall function," says Kim Janda, Ph.D., who holds the Ely R. Callaway, Jr. Chair in Chemistry at TSRI.

This process is the chemical equivalent of cooking and is the same reaction that browns seared sugars and that causes food to age and spoil. Furthermore, the "cooking" of proteins is just the tip of the iceberg - nornicotine also reacts with commonly prescribed steroids, like cortisone and prednisone, potentially making them more toxic or compromising the effectiveness and safety of these drugs.

How Nornicotine "Cooks" Proteins

The chemical nornicotine attaches itself "covalently" (permanently) to steroids and to certain amino acids on the surface of proteins. These modified steroids and proteins can then interact with other chemicals in the body. Significantly, nornicotine-modified proteins can react to form a variety of compounds known as advanced glycation endproducts.

"These advanced glycation endproducts are not supposed to be [present in your body] naturally," says Tobin Dickerson, a Ph.D. student in TSRI's Kellogg School of Science and Technology. "Your body is not prepared for them."

Advanced glycation endproducts have previously been implicated in numerous diseases including diabetes, cancer, atherosclerosis, and Alzheimer's disease. Dickerson and Janda's study shows a direct link between tobacco use and the development of these advanced glycation endproducts.

When they tested the blood of smokers and non-smokers, they found that the smokers had higher levels of the nornicotine-modified proteins than non-smokers. The smokers also had higher levels of the advanced glycation endproducts.

The persistence of nornicotine in the bloodstream - as opposed to nicotine, which quickly disappears after cessation of smoking - may also suggest a role for nornicotine in contributing to the biological mechanisms of tobacco addiction, since the nornicotine provides a long-lived source of nicotine-like molecules.

The work highlights the need for more studies into the consequences of exposing the human body to nicotine metabolites, like nornicotine.

The article, "A previously undescribed chemical link between smoking and metabolic disease" was authored by Tobin J. Dickerson and Kim D. Janda and appears in the October 28, 2002 online edition of the journal Proceedings of the National Academy of Sciences. The article will appear in print later this year.

This work was supported by The Skaggs Institute for Research.


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