Nicotine: From Discovery to Biological Effects

Abstract

Nicotine, the primary psychoactive agent in tobacco leaves, has led to the widespread use of tobacco, with over one billion smokers globally. This article provides a historical overview of tobacco and discusses tobacco dependence, as well as the biological effects induced by nicotine on mammalian cells. Nicotine induces various biological effects, such as neoangiogenesis, cell division, and proliferation, and it affects neural and non-neural cells through specific pathways downstream of nicotinic receptors (nAChRs). Specific effects mediated by α7 nAChRs are highlighted. Nicotine is highly addictive and hazardous. Public health initiatives should prioritize combating smoking and its associated risks. Understanding nicotine's complex biological effects is essential for comprehensive research and informed health policies. While potential links between nicotine and COVID-19 severity warrant further investigation, smoking remains a significant cause of morbidity and mortality globally. Effective public health strategies are vital to promote healthier lifestyles.

Keywords: cardiovascular diseases; cell proliferation; cognition; dependence; lung cancer; neo-angiogenesis; nicotine; nicotinic receptor; tobacco.

Figure 1

Schematic representation of nicotine’s effects. Nicotine is a tertiary amine consisting of a pyridine and a pyrrolidine ring. (S)-nicotine, which is found in tobacco, selectively binds to nAChRs in a stereoselective manner. The nAChR complex comprises five subunits and is present in both neuronal and non-neuronal cells. There are up to nine α subunits (α2 to α10) and three β subunits (β2 to β4). The most prevalent receptor subtypes in the human brain are α4β2, α3β4, and α7 (homomeric). α4β2* (the asterisk indicates the possible presence of other subunits in the receptor) is the predominant subtype in the human brain, and is believed to be the primary receptor responsible for nicotine dependence. The α3β4 nAChR is thought to mediate the cardiovascular effects of nicotine, while α7 is the most abundant in non-neuronal cells and mediates nicotine’s biological effects, such as cell proliferation, neo-angiogenesis, and resistance to drug-induced apoptosis. Despite their diversity, all mammalian nAChR subtypes are permeable to Na⁺, K⁺, and Ca²⁺ ions. nAChRs can exist in different conformational states, including closed, open, and conducting states (activated by ligand binding such as Ach or nicotine), as well as desensitized states (closed and unresponsive to ligand binding). The physiological ligand for nAChRs is ACh. When ACh or nicotine (a receptor agonist) binds to the receptor, the ion channel briefly opens, allowing the flow of cations and altering the membrane potential, typically resulting in depolarization. The channel can then return to its resting state (closed and responsive to activation) or enter a desensitized state, where it is unresponsive to ACh, nicotine, or other agonists. Nicotine is rapidly and extensively metabolized by the liver, primarily by the liver enzyme CYP2A6 (and to a lesser extent by CYP2B6 and CYP2E1), to form cotinine. Cotinine is subsequently metabolized exclusively or nearly exclusively to trans-3′-hydroxycotinine (3HC) by CYP2A6. The half-life of nicotine averages approximately 2 h, while the half-life of cotinine averages around 16 h. For more comprehensive explanations and references, please refer to the accompanying test.