Mimicking a good gene defect

Drug therapy designed to make quitting smoking easier.

You’re a smoke, but your partner isn’t and never has been. Why? And why is it so hard for you to quit, but your friend did it without as much trouble?

Some of it probably has to do with CYP2A6.

When nicotine from a cigarette enters the body, the drug shoots up to your brain and then to your liver. CYP2A6 is an enzyme found in the liver that helps you expel the nicotine from your body, by way of your kidneys.

The problem with CYP2A6’s efficiency in metabolizing nicotine so quickly is that once the drug is expelled from your body, you will soon crave more. So you will re-fill your supply with another smoke, then another. The danger, of course, is that after years of feeding the addiction, you have a good probability of suffering debilitating and fatal tobacco-related diseases. But in the late 1990s, a U of T team found that if you have a defective version of CYP2A6, you’re in much better shape for not becoming a smoker, or if you do smoke, you will smoke a lot less.

“The defective version of CYP2A6 actually slows down the metabolism of nicotine, so it stays in your body longer,” says Rachel Tyndale, associate professor of pharmacology, who made the discovery with Edward Sellers, also of pharmacology. “This means that you will have less frequent cravings for nicotine. Or it can result in greater negative effects of nicotine, such as nausea and dizziness, which can turn you off smoking completely.”

The presence of CYP2A6 is a fascinating story of adaptation. Tyndale says it is thought that when plants and animals separated early in the evolutionary process, the plants, as living beings themselves, didn’t want to be eaten so they developed toxins to repel animals. Animals reacted by developing enzymes that would act as a defense system and allow the body to get rid of the toxins quickly. One of those enzymes is CYP2A6.

“It’s a remarkable example of evolution at work. But this enzyme actually increases smoking, while its defective variation decreases the need to smoke. And not everyone has the defect. So we’re trying to imitate the defect to help people quit smoking more easily.”

Tyndale, Sellers and colleagues Ewa Hoffmann, Sharon Miksys, Yushu Rao and Helma Nolte have been pursuing a method of mimicking the action of the genetic defect and producing a drug therapy that would either replace or be used in conjunction with current nicotine replacement methods, such as the nicotine patch. “A lot of methods don’t work as well as they could because they are one-size-fits-all approaches. Every smoker has different nicotine needs, so quitting will be much easier if the therapy can be customized. Our drug therapy will allow a smoker to adjust intake of nicotine to when they need it at different times during the day.”

Tyndale and Sellers are carrying out their research with support from the Canada Research Chairs, the Canadian Institutes of Health Research and the Centre for Addiction and Mental Health. They have also formed a company, Nicogen, to develop the drug therapy. Their patents are currently issuing.

Tyndale points out that approximately 35 per cent of smokers make a serious attempt to quit each year, but only five per cent are successful. “Quitting smoking is a tough battle. But we believe our process will give people a much better chance of staying off tobacco for good.”