The effect of tobacco on lung cancer risk depends on CYP2D6 activity.

The genetically determined P450 CYP2D6 activity is suspected to be involved in lung carcinogenesis by activating carcinogens contained in tobacco smoke. Therefore, lung cancer risk should depend on both smoking exposure and CYP2D6 activity. The extent to which CYP2D6 activity, determined by using dextromethorphan, could modify the effect of tobacco was evaluated from a study on 128 lung cancers and 157 controls. A strong interaction was observed; the effect of tobacco on lung cancer risk rose with increasing CYP2D6 activity (P < 0.001). Increasing levels of smoking increased lung cancer risk only among smokers with the highest CYP2D6 activity, and CYP2D6 was a risk factor only among heavy smokers. Smokers with both the highest CYP2D6 activity and daily tobacco consumption were at very high risk for lung cancer. These results may explain discrepant results of previous studies on the association between CYP2D6 activity and lung cancer.