It's not just the nicotine, it's the nornicotine, too. That little prefix - n-o-r - in front of a molecule's name means that the protein, hormone or whatever has lost one of its methylene groups. Nornicotine is a two-edged case in point.
"Nornicotine is just a metabolite of nicotine," explained biochemist Tobin Dickerson, at the Scripps Research Institute in La Jolla, Calif. "It's one of the minor metabolites, structurally being the loss of a methyl group. So structurally nicotine and nornicotine are very similar. Nornicotine does occur naturally in tobacco leaves," he continued, "in a process similar to metabolism. The plant also breaks down nicotine to some small extent, just as your body breaks down nicotine to nornicotine.
"Research into nicotine metabolites was going on actively in the 1970s," he noted, "but nornicotine and its role - not only in nicotine addiction but the consequences of nornicotine - have only recently been studied. The first data to show that nornicotine is also psychologically active, is in a sense addictive, were only published in 1998. So it's recently like a renaissance, looking at these nicotine metabolites."
Dickerson, a Scripps Ph.D. candidate, is lead author of a paper in the Proceedings of the National Academy of Sciences (PNAS), released online Oct. 29, 2002. Its title: "A previously undescribed chemical link between smoking and metabolic disease." Its senior author is Kim Janda, an endowed professor of chemistry at Scripps.
"The overall finding of our paper," Dickerson told BioWorld Today, "was that an exogenous secondary metabolite can chemically react with proteins in vivo, leading to these aberrant protein glycation products. What this means is that a compound not supposed to be there in your body is getting into your bloodstream via smoking. And there it is altering proteins so that they could potentially lose function. Common prescribed drugs such as the steroid prednisone can also undergo modification," he added. "In that case its altered drug activity becomes such that the drug may no longer do what it was intended to. For all we know at this point, it could become better or worse.
"Usually people look at this sort of process in the context of proteins interacting with other proteins. In this case we're looking at a small molecule, nornicotine, that just isn't supposed to be there. You're ingesting it through smoking, or tobacco use. As a result, this sort of chemistry, called glycation, is implicated in diabetes - the most common scenario - and also in Alzheimer's disease, atherosclerosis and cancer."
Glycated Drugs Discombobulate Prednisone
"We were the people who discovered this prednisone connection. People had known about this sort of chemistry for steroids, but always in the context of proteins - a protein and a steroid would interact. We tried to repeat these experiments and see if nornicotine and a steroid could also react. Instead of just the end-product, we also saw a second product forming, by glycation. That was novel, never seen before.
"What we noticed was that nornicotine is similar to the structures found in these glycation products that had been published before. Glycation is the process by which glucose gets bound covalently - irreversibly - to a sugar. In essence it's similar to when you age food, when you bake bread and it browns on top. It's like caramelization, similar to that kind of chemistry but not identical. Glycation has the role of generating flavor in a lot of foods - roasted coffee, baked breads, grilled meats. In vivo, glycation has been known for well over 100 years. And in the past 20 years in humans, glycation has been found to be a process that actually can be detrimental in vivo. Because what happens is you start cross-linking one protein with another, and as a result that's where a lot of these complications arise in diseases."
Does nornicotine play a role in addiction? "It certainly could," Dickerson suggested. "We're exploring right now whether the prevailing modified proteins that we report in the paper are playing a role in addiction. We're currently looking to see if advanced glycation end-products [AGEs] such as nornicotine are potentially long-lived sources of nicotine in the blood. Nicotine's half-life in the body is about an hour. Nornicotine's glycation products have a half-life measured in weeks. So essentially from one dose of nicotine, smokers acquire a long-lived source of these nicotine-like breakdown compounds."
Dickerson and his co-authors are "also exploring tobacco addiction and treatment in Alzheimer's disease [AD]. It's pretty well known," he pointed out, "that such therapy could potentially be beneficial for AD patients. But it's very debatable, and there's been a lot of back and forth on the issue. We have some preliminary data that might just be important there. This type of glycation chemistry, and nornicotine, could play roles in AD. As for a putative mechanism of any benefit in AD," he observed, "what we're looking at is the formation of neuritic plaques that accumulate in the Alzheimer's brain, and potentially seeing slower polymerization, essentially reduced plaques. But at this point," Dickerson demurred, "that's very, very preliminary."
Therapeutic Gig For Tobacco In Alzheimer's?
"For the near or medium future," he went on, "unfortunately, nornicotine is an addictive compound, so treatment with it as a therapeutic would obviously not be an approach for any sort of drug to treat these glycation diseases. However, understanding the mechanism of how this small molecule can participate in glycation chemistry could lead to specific pharmaceuticals. Currently on the market there are drugs that treat some of the side effects of diabetes by breaking these glycation products apart. So potentially, that's our current direction.
"The biggest thing is that smoking is a very common occurrence in society. Its consequences are well known in the context of nicotine alone. But there are these metabolites that are really reactive and clearly can do things. The public should at least be aware that exposure to these could also be detrimental, and could extend as far as nicotine patches and nicotine gum, where the tar has been reduced but the AGE components remain. However, exposure to nicotine itself and its metabolites," Dickerson concluded, "could also be more detrimental than previously thought."