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Nov/Dec 2000
Vol. 3, No. 9, pp. 27-28, 30

to your health

Psoriasis drug inhibits nicotine metabolism

The compound methoxsalen may help smokers quit.Opening Art

Your father, an avid smoker, kicked the habit at the age of 68, cold turkey. Your sister quit after a few months of chewing nicotine gum—her hand waving celery sticks between fingers once graced by a smoldering cigarette. Your co-worker, a former pack-a-day smoker, used hypnotherapy to quit and has been on a soapbox ever since.

But you’re a different story. You tried nicotine gum to no avail, and then there was the patch. Thankfully, you gave up the patch when you realized that smoking while wearing it defeated the purpose and might even be downright dangerous.

Genetic destiny?
Many individuals fall into this last category of smokers—people who just can’t seem to butt out. For these people, the inability to quit is proving to be more a product of genetics than a weakness of character or lack of motivation.

It has long been known that nicotine is the culprit in establishing and maintaining tobacco addiction. However, the rate at which one smoker metabolizes nicotine compared with another separates those who become heavily dependent on cigarettes from those who remain “social
Figure 1. Schematic representation of Caco-2 permeablility assay.

Figure 1. Block that conversion. By inhibiting CYP2A6 with methoxsalen, Toronto researchers hope to slow the conversion of nicotine to cotinine and thus alter the smoking habits of nicotine-dependent individuals.

” smokers.

The key player appears to be a liver enzyme called CYP2A6, which is a member of the cytochrome P-450 family of proteins. CYP2A6 governs the metabolism of nicotine to cotinine in a two-step process (see Figure 1). Three versions of the gene encoding CYP2A6 have been identified in various populations: one normal, or wild-type, version and two that are functionally impaired. The wild-type enzyme actively metabolizes nicotine, clearing it rapidly from the body. Thus, a smoker needs to light up frequently to maintain blood and brain nicotine levels and keep withdrawal symptoms at bay. However, CYP2A6 is a double-edged sword in that it also activates procarcinogens found in tobacco smoke into bona fide carcinogens.

For individuals with a defective copy of the gene, however, nicotine metabolism is impaired, and the smoker is protected from heavy dependency. As a result, smokers with the defective gene are less likely to take up the habit. They smoke less even if they do become dependent, and they are less likely to develop smoking-related cancers and medical conditions because procarcinogen activation is believed to be less likely to occur.

Cessation assistance
Since reporting these findings two years ago (1), Edward Sellers, a pharmacologist at the University of Toronto, and his colleagues have found an inhibitor that can gum up the activity of CYP2A6 and help heavily dependent smokers get a handle on their addiction. “Nicotine leaves the body rapidly, which is why heavy smokers light up every hour—to fill up their nicotine tank. If you don’t metabolize it very well due to lack of enzyme, nicotine enters the body and stays there for a long time,” says Sellers.

After screening more than 200 compounds, Sellers and his group found that methoxsalen, a medication already approved for treating psoriasis, was an effective inhibitor of CYP2A6 activity. In one study, 17 smokers who were not intending to quit were given tablets containing 30, 10, or 3.5 mg of methoxsalen or a placebo orally, along with a 4-mg nicotine tablet. Blood nicotine levels were measured at 30-min intervals over 3 h. As expected, those who received the higher doses of methoxsalen had nicotine levels that were twice as high as those who took the 3.5-mg methoxsalen or placebo tablets, and they reported they did not feel the urge to light up as often (see Figure 2).

In a second study, smokers were given either 30-mg methoxsalen tablets or a placebo, along with a nicotine tablet or a placebo, and were made to abstain for 1 h. They were then permitted to smoke to their hearts’ content for 90 min. Again, those who received the inhibitor smoked fewer cigarettes and took fewer puffs (2).

“If we gave oral nicotine and the inhibitor, smoking decreased by 50%,” says Sellers. “In those who received the inhibitor alone [and received a placebo tablet instead of the nicotine tablet], smoking decreased 30%.”

Figure 1. Schematic representation of Caco-2 permeablility assay.

Figure 2. Mind (and body) over matter. (A) Patients given a 4-mg dose of nicotine with tablets containing 10 mg or 30 mg of methoxsalen (M10 and M30, respectively) showed higher mean blood nicotine levels and a dramatically reduced urge to smoke compared with patients receiving nicotine and a placebo (P) or 3.5 mg of methoxsalen (M3.5) (B) Similarly, over a 3-h time span, patients receiving the higher doses of the CYP2A6 inhibitor showed an improved ability to maintain their blood nicotine levels. (Adapted from Sellers, E.M. et al. Chin. Pharmacol. Ther. 2000, 68, 35-43.)

As a drug delivery system, cigarettes deliver nicotine to the brain faster than any intravenous system, says Rachel Tyndale, a member of the research team and a pharmacologist at the Centre for Addiction and Mental Health in Toronto. As nicotine enters their body, smokers experience an immediate spike of the drug, followed by a drop as it is converted to cotinine. Nicotine patches, sprays, and gum, in contrast, provide a steady source of nicotine that does not mimic the spikes to which the smoker has become accustomed. The use of an inhibitor on its own could, at the very least, decrease smoking frequency by helping to maintain nicotine levels in the body for longer periods. Smokers who use an inhibitor together with other replacement therapies may find it easier to stick to treatment and learn behavior modification techniques.

When individuals begin to smoke, they quickly become conditioned to receiving the nicotine reward, says Tyndale. “Individuals smoking approximately 20 cigarettes a day, using 20 puffs per cigarette, are doing this behavior 400 times a day.” This repeated action is reinforced by the burst of nicotine that rewards the behavior, she adds.

While nicotine is generally regarded as relatively harmless, the carbon monoxide, tars, nitrosamines, free radicals, and thousands of other chemicals—not to mention 30 known carcinogens—found in cigarettes make smoking a health hazard unlike any other. “It’s a contaminated delivery system—you would never be allowed to put those chemicals in any other drug today,” says Tyndale. “Cigarette companies have put a lot of research into designing just about the most addictive format for nicotine delivery.”

Changing behavior
Undoing that addiction is another matter entirely. Current cessation therapies work well for some and not for others because of huge variations in blood nicotine levels. Tyndale believes that this is where their inhibitor enters the picture. Giving an inhibitor to people to slow down nicotine metabolism makes a diverse population now quite similar. With blood nicotine levels maintained and the burning desire to light up quenched, smoking cessation therapies have a greater likelihood of success. Even those who do not quit might, at the very least, scale back the number of cigarettes they smoke each day. “The goal is to start to retrain behavior and cut down the risk of exposure to the carcinogens,” Tyndale says.

But this “harm reduction” approach to treating addiction has its critics, says John Hughes, a professor of psychiatry and an expert on tobacco addiction at the University of Vermont in Burlington. Some argue that eliminating the drug and not simply lessening the behavior should be the goal.

Hughes believes that the Toronto group’s studies are a much-needed approach. “Eighty percent of smokers want to quit—that’s true. In any year, only a third will try. The average smoker tries to quit only once every three years, so people have now started saying that the world’s best treatment is only going to help 10% to 20%.”

Given that there are 50 million smokers in the United States—and that there are more smokers in China than there are people in the United States—there is clearly room for improvement. In the 1960s, 45% of Americans were smokers. By the 1990s, that figure dropped to 25%, but it has remained steady ever since and is even increasing among groups such as teenage girls. Hughes believes that smokers who have quit have done so because they can, whereas those remaining are “genetically wired” to be nicotine-dependent. “There are some smokers who are not going to quit smoking unless they get treatment,” he says. “We’ve now got to change strategy and start offering treatment to those in whom motivation is not enough.”

Karl Fagerstrom, a behavioral scientist and consultant in Helsingborg (Sweden), was involved in the early trials of the current nicotine replacement therapies. He agrees that an inhibitor will be of enormous help to some individuals, pointing out that for some smokers, structural changes that occur in the brain in response to nicotine do not necessarily return to normal. Furthermore, nicotine is a structural mimic of the neurotransmitter acetylcholine, binding to its receptors in the brain.

“We have a whole cascade of neural transmitters, which leads to a number of [systemic] effects,” says Fagerstrom, adding that nicotine increases metabolism by 5% to 8%, lessens irritability, improves mood, and enhances concentration. Consequently, when smokers quit, they are faced with a nervous system redesigned for nicotine and are unable to function well without the drug. Cigarette manufacturers are currently developing cigarettes that distill nicotine rather than burn tobacco and its harmful constituents. “We’ve never had an instance where a drug has been so entrenched in society that you’re not going to get rid of it,” says Hughes. Like it or not, nicotine addiction won’t ever go away.

In the meantime, Sellers says that longer-term studies in the pipeline are looking at the safety and efficacy of methoxsalen and other potent inhibitors that he and his colleagues have found. For those who cannot seem to kick the habit, this may be their best hope.


  1. (1) Pianezza, M. L.; Sellers, E. M.; Tyndale, R. F. Nature 2000, 393, 750.
  2. (2) Sellers, E. M.; Kaplan, H. L.; Tyndale, R. F. Clin. Pharmacol. Ther. 2000, 68, 35–43.


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