Molecule of the Month: Nicotine, Cancer, and Addiction

Vaping and tobacco products represent serious dangers to health, particularly among teens and young adults. Continued usage of these products leads to chronic exposure to hazardous chemicals and millions of deaths worldwide every year. The nicotine in vapes and tobacco is a driving force in habitual use of these products. Although nicotine is not naturally found in humans, it binds to the acetylcholine receptor in the brain and activates the reward system in our central nervous system. This phenomenon induces users to continue consuming nicotine, leading to addiction.

Nicotinic acetylcholine receptors are funnel-shaped molecules with an ion channel running through the center (shown here from PDB entry 6pv7). A specific neurotransmitter molecule called acetylcholine functions as a key to unlock these ion channels. Once opened, the channels allow ions such as sodium, calcium, and potassium to pass through, converting a chemical signal across the cell membrane into an electrical signal. Nicotine from smoking or vaping products can act as an alternative key for opening these channels, and is reflected in the name nicotinic acetylcholine receptors.

In human cells, nicotinic acetylcholine receptors are pentameric, made up of five subunits. There are 16 types of receptor subunits that can combine in myriad ways to assemble the pentameric receptor. Nicotine molecules bind at the interface between two different subunits. Depending on the combinations of distinct subunits present in a given receptor, there are differences in binding affinities and responses to the drug. Human genetic studies and mouse models of nicotine exposure show that some of these subunit combinations may lead to higher susceptibility of nicotine addiction and severe withdrawal symptoms. Structures of the various types of nicotinic acetylcholine receptors can help us understand how different combinations of subunits interact with acetylcholine and nicotine molecules.

Like most drugs, the effects of nicotine wear off as special enzymes break it down into molecules that can be excreted. Cytochrome P450 enzymes play a major role in metabolizing and detoxifying nicotine. These enzymes add oxygen to nicotine to make it easier to excrete. However, cytochrome P450 enzymes can have dangerous effects. They can activate nitrosamines, molecules derived from nicotine in vaping and tobacco products. One of the most common nitrosamines, NNK, is a procarcinogen that can be activated by a cytochrome P450 enzyme (shown here in PDB entry 4ejh), releasing activated molecules that interact with DNA and can cause mutations in cancer-related genes. In this way, persistent use of vaping and other nicotine-containing products continually exposes people to dangerous carcinogens that can promote tumor formation over time.