Study Shows Nicotine By-Product Reacts with Proteins
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. candidate 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 Chemical
Biology.
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