The Metabolism of Nicotine 


1 - Absorption of nicotine

Absorption of nicotine through cellular membranes depends on the pH. If the pH is acidic, nicotine is ionized and does not easily pass through membranes. At physiologic pH (pH = 7.4), 31% of nicotine is not ionized and easily passes through membranes.

The tobacco smoke pH is acidic, and this acidity only allows a little absorption in the mouth. Inhalation is therefore necessary to allow nicotine to be absorbed by the huge area of alveolar epithelium. In the lungs, nicotine is quicklyt absorbed by the systemic circulation. This absorption is easy because the blood flow is high in the lung capillaries : a volume equal to the blood volume of the body passes each minute. So, the rate of nicotine qickly rises when a cigarette is smoked. Absorbed nicotine is rapidly distributed among all the organs, and it reaches the brain within only  ten seconds.
 
 

2 - Action on nicotinic receptors

The active form of nicotine is a cation whose charge is located on the nitrogen of the pyrrole cycle. This active form is very close to acetylcholine. It has been demonstrated that nicotine interferes with acetylcholine, which is the major neurotransmitter of the brain. Acetylcholine can bind to two different kinds of receptors: nicotinic receptors, which are activated by nicotine, and muscarinic receptors, which are activated by muscarine. Nicotine and muscarine are thus specific agonists of one kind of cholinergic receptors (an agonist is a molecule that activates a receptor by reproducing the effect of the neurotransmitter.)

Nicotine competitively binds to nicotinic cholinergic receptors. The binding of the agonist to the nicotinic receptor triggers off a conformation change of the architecture of the receptor, which opens the ionic channel during a few milliseconds. This channel is selective for cations (especially sodium). Its opening thus leads to a brief depolarization. Then, the channel closes and the receptor transitionally becomes refractory to agonists. This is the state of  desensitization. Then, the receptor  usually goes back to a state of rest, which means that it is closed and sensitive to the agonists. In case of continuous exposure to agonists (even in small doses), this state of desensitization will last long (long-term inactivation).

Operating cycle of a nicotinic receptor:
 
 

Physiological normal conditions: After the opening of the canal by binding to acethylcholine, the receptor becomes desensitized before it goes back to the state of rest or it is regenerated.
 
 

Continuous exposure to tobacco: Nicotine substitutes for acetylcholine and over stimulates the nicotinic receptor. Then, the receptor is long-term inactivated and its regeneration is prevented by nicotine.

 

3 - Tolerance and dependence on nicotine

Nicotine rises the stimulation of nicotinic receptors. The excessive and chronic activation of these receptors is balanced by a down-regulation in the number of active receptors. The reduction of the number of active receptors reduces the psychotropic effect of nicotine. Due to the phenomenon of tolerance, the smoker needs to smoke more and more cigarettes to keep a constant effect.

Nicotine activates dopamine systems within the brain. Dopamine is a neurotransmitter which is directly responsible for mediating the pleasure response. Nicotine triggers off the production of dopamine in the nucleus accumbens. A prolonged exposure of these receptors to nicotine reduces the efficiency of dopamine by cutting down the number of available receptors. Consequently, more and more nicotine is needed to give the same pleasurable effect.

After a brief period of abstinence (overnight for instance), the brain concentration of nicotine lowers and allows a part of the receptors to recover their sensibility. The return to an active state rises the neurotransmission to an abnormal rate. The smoker feels uncomfortable, which induces him to smoke again. The first cigarette of the day is the most pleasant because the sensibility of the dopamine receptors is maximal. Then, the receptors are soon desensitized and the pleasure wears off. This is the vicious circle of smoking.
 

4 - Chemical transformations undergone by nicotine

Nicotine is mainly transformed in the liver, but also in the lungs and the kidneys. The primary metabolites of nicotine are cotinine and  nicotine N-oxide, which are some products of the hepatic oxidation of nicotine by  P-450 cytochrome.

How can nicotine be dangerous for the body?

Nicotine and its metabolites may be dangerous for the body. Actually, nicotine is a strong carcinogen. In fact, nicotine can undergo several kinds of transformation like a pyrrole cycle opening. The methyl group on this cycle can become a very powerful alkylating agent when removed from the cycle.

The amine function of nicotine may react with nitrogen monoxide or with nitrous acid in order to form a "nitrosonium" type molecule. This compound may then be transformed by the body, which means oxidized and opened. This opening leads to two isomers, two "nitrosamino" type molecules (R2N-N=O) where one of the two R group is a methyl. This reaction occurs as follows:
 

A = 4 (N-methyl-N-nitrosamino)-1-(3-pyridyl)-butan-1-one              B = 4 (N-methyl-N-nitrosamino)-4-(3-pyridyl)-butanal

In acidic medium, the oxygen of the "nitrosamino" group is protonated and the double bond moves to the central nitrogen, which becomes positively charged. This new molecule is a methyl source. The "nitrosamino" group can then react with another amine, which removes the positive charge from the nitrogen. If the amine that reacts is a part of the structure of the DNA, an irreversible alkylation of the DNA occurs:
 
 


This alkylation is really  noxious and may help in the development of cancer as it prevents the normal development of the cell.