Nicotine is an alkaloid found in the nightshade
family of plants (Solanaceae) that acts as a nicotinic acetylcholine agonist
and a monoamine oxidase inhibitor[citation needed]. The biosynthesis takes
place in the roots and accumulation occurs in the leaves of the Solanaceae. It
constitutes approximately 0.6–3.0% of the dry weight of tobacco and is present
in the range of 2–7 µg/kg of various edible plants. It functions as an
antiherbivore chemical; therefore, nicotine was widely used as an insecticide
in the past and nicotine analogs such as imidacloprid are currently widely
used.
Nicotine is a
hygroscopic, oily liquid that is miscible with water in its base form. As a
nitrogenous base, nicotine forms salts with acids that are usually solid and
water soluble. Nicotine easily penetrates the skin. As shown by the physical
data, free base nicotine will burn at a temperature below its boiling point,
and its vapors will combust at 308 K (35 °C; 95 °F) in air despite a low vapor
pressure. Because of this, most of the nicotine is burned when a cigarette is
smoked; however, enough is inhaled to cause pharmacological effects.
Optical activity
Nicotine is
optically active, having two enantiomeric forms. The naturally occurring form
of nicotine is levorotatory with a specific rotation of [α]D = –166.4°
((−)-nicotine). The dextrorotatory form, (+)-nicotine is physiologically less
active than (–)-nicotine. (−)-nicotine is more toxic than (+)-nicotine.[17] The
salts of (+)-nicotine are usually dextrorotatory.
Biosynthesis
Pharmacokinetics
As nicotine
enters the body, it is distributed quickly through the bloodstream and crosses
the blood–brain barrier reaching the brain within 10–20 seconds after
inhalation. The elimination half-life of nicotine in the body is around two
hours.
The amount of
nicotine absorbed by the body from smoking depends on many factors, including
the types of tobacco, whether the smoke is inhaled, and whether a filter is
used. For chewing tobacco, dipping tobacco, snus and snuff, which are held in
the mouth between the lip and gum, or taken in the nose, the amount released
into the body tends to be much greater than smoked tobacco.[clarification
needed][citation needed] Nicotine is metabolized in the liver by cytochrome
P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is
cotinine.
Other primary
metabolites include nicotine N'-oxide, nornicotine, nicotine isomethonium ion,
2-hydroxynicotine and nicotine glucuronide. Under some conditions, other
substances may be formed such as myosmine.
Glucuronidation
and oxidative metabolism of nicotine to cotinine are both inhibited by menthol,
an additive to mentholated cigarettes, thus increasing the half-life of
nicotine in vivo.
In the central
nervous system
By binding to
nicotinic acetylcholine receptors, nicotine increases the levels of several
neurotransmitters – acting as a sort of "volume control". It is thought
that increased levels of dopamine in the reward circuits of the brain are
responsible for the apparent euphoria and relaxation, and addiction caused by
nicotine consumption. Nicotine has a higher affinity for acetylcholine
receptors in the brain than those in skeletal muscle, though at toxic doses it
can induce contractions and respiratory paralysis.[30] Nicotine's selectivity
is thought to be due to a particular amino acid difference on these receptor
subtypes.
Tobacco smoke
contains anabasine, anatabine, and nornicotine.[citation needed] It also
contains the monoamine oxidase inhibitors harman and norharman.These
beta-carboline compounds significantly decrease MAO activity in smokers.MAO
enzymes break down monoaminergic neurotransmitters such as dopamine,
norepinephrine, and serotonin. It is thought that the powerful interaction
between the MAOI's and the nicotine is responsible for most of the addictive properties
of tobacco smoking.The addition of five minor tobacco alkaloids increases
nicotine-induced hyperactivity, sensitization and intravenous self-administration
in rats.
Chronic nicotine
exposure via tobacco smoking up-regulates alpha4beta2* nAChR in cerebellum and
brainstem regions but not habenulopeduncular structures.Alpha4beta2 and
alpha6beta2 receptors, present in the ventral tegmental area, play a crucial
role in mediating the reinforcement effects of nicotine.
In the sympathetic nervous system
Nicotine also
activates the sympathetic nervous system,[40] acting via splanchnic nerves to
the adrenal medulla, stimulates the release of epinephrine. Acetylcholine
released by preganglionic sympathetic fibers of these nerves acts on nicotinic
acetylcholine receptors, causing the release of epinephrine (and
norepinephrine) into the bloodstream. Nicotine also has an affinity for
melanin-containing tissues due to its precursor function in melanin synthesis
or due to the irreversible binding of melanin and nicotine. This has been
suggested to underlie the increased nicotine dependence and lower smoking
cessation rates in darker pigmented individuals. However, further research is
warranted before a definite conclusive link can be inferred.
Effect of nicotine on chromaffin cells.
In adrenal medulla
By binding to
ganglion type nicotinic receptors in the adrenal medulla nicotine increases
flow of adrenaline (epinephrine), a stimulating hormone and neurotransmitter.
By binding to the receptors, it causes cell depolarization and an influx of
calcium through voltage-gated calcium channels. Calcium triggers the exocytosis
of chromaffin granules and thus the release of epinephrine (and norepinephrine)
into the bloodstream. The release of epinephrine (adrenaline) causes an
increase in heart rate, blood pressure and respiration, as well as higher blood
glucose levels.
Nicotine is the
natural product of tobacco, having a half-life of 1 to 2 hours. Cotinine is an
active metabolite of nicotine that remains in the blood for 18 to 20 hours,
making it easier to analyze due to its longer half-life.
Sumber: en.wikipedia.org
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.
Sumber : http://www.chm.bris.ac.uk
when nicotine reacts with nitrogen monoxide or nitrous acid to form nitrosonium, and oxidation reactions in the body that opens cyclic bond formed two isomeric compounds, namely A = 4 (N-methyl-N-nitrosamines) -1 - (3-pyridyl)-butane-1 -one and B = 4 (N-methyl-N-nitrosamines) -4 - (3-pyridyl)-butane. How the reaction mechanism that can produce compound A and the reaction mechanism how well that can produce compound B?
BalasHapusDini i've read an article and i found "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.
BalasHapusThe 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......." for more complete you may open this link www.chm.bris.ac.uk/motm/nicotine/E-metabolisme.html
hy dini
BalasHapusI read your blog
functions as an antiherbivore chemical; therefore, nicotine was Widely used as an insecticide in the past and nicotine analogs such as imidacloprid are currently Widely used.
but I have a problem
how to work the nicotine while in the insect body?
Neonicotinoids are a class of neuro-active insecticides chemically related to nicotine. The development of this class of insecticides began with work in the 1980s by Shell and the 1990s by Bayer.[1] The neonicotinoids were developed in large part because they show reduced toxicity compared to previously used organophosphate and carbamate insecticides. Most neonicotinoids show much lower toxicity in mammals than insects, but some breakdown products are toxic.ticides introduced in the last 50 years, and the neonicotinoid imidacloprid is currently the most widely used insecticide in the world. Recently, the use of some members of this class has been restricted in some countries due to evidence of a connection to honey-bee colony collapse disorder.Neonicotinoids, like nicotine, are nicotinic acetylcholine receptor agonists. This receptor is normally activated by the neurotransmitter acetylcholine. These receptors are located in both the central and peripheral nervous systems of mammals but are limited to the CNS in insects. While low to moderate activation of these receptors causes nervous stimulation, high levels overstimulate and block the receptors.[3][6] This receptor blockage causes paralysis and death. Normally, acetylcholine is broken down by acetylcholinesterase to terminate signals from these receptors. However, acetylcholinesterase cannot break down neonicotinoids, and the binding is irreversible.[6] Because most neonicotinoids bind much more strongly to insect neuron receptors than to mammal neuron receptors, these insecticides are selectively more toxic to insects than mammals.[7]
Hapus[edit] Basis of selectivity
R-nicotine
Desnitro-imidacloprid
R-nicotine (top) and desnitro-imidacloprid are both protonated in the body
Most neonicotinoids, such as imidacloprid, show low affinity for mammalian nicotinic acetylcholine receptors (nAChRs) while exhibiting high affinity for insect nAChRs.[3][8] Mammals and insects have structural differences in nAChRs that affect how strongly particular molecules bind, both in the composition of the receptor subunits and the structures of the receptors themselves.[7][8] Nicotine, like the natural ligand acetylcholine, has a positively charged nitrogen (N) atom at physiological pH.[3][7] A basic nitrogen will become positively charged in neutral aqueous solution because it is protonated by water. This positive charge gives these compounds a strong affinity to mammalian nAChRs. At the same time, the charge on nicotine lowers its effectiveness as an insecticide, because the blood–brain barrier prevents free access of ions to the central nervous system, and insect nAChRs are only present in the central nervous system.[3][7] The blood–brain barrier does not prevent nicotine poisoning in mammals, because mammalian nAChRs are located in the peripheral nervous system and are necessary for vital functions such as breathing. The low mammalian toxicity of imidacloprid can be explained in large part by its lack of a charged nitrogen atom at physiological pH. The molecule shows weak affinity to mammalian nAChRs but strong affinity for insect nAChRs. Furthermore, the uncharged molecule can penetrate the insect blood–brain barrier, while the human blood–brain barrier filters it.However, desnitro-imidacloprid, which is formed in a mammal's body during metabolism as well as in environmental breakdown, has a charged nitrogen and shows high affinity to mammalian nAChRs. Desnitro-imidacloprid is quite toxic to mice.you can read a more detailed article on http://en.wikipedia.org/wiki/Neonicotinoid
din, after reading your article, i found some problems :
BalasHapusnicotine may undergo some kind of transformation such as the opening of the pyrrole cycle. explain how the opening cycle pyrrole on nicotine?? and please explain other types of transformation that nicotine do?
then why the methyl group on pyrrole opening cycle can be very strong alkylating agent when removed from the cycle??
dini, i want to ask u about cotinine. Cotinine is an active metabolite of nicotine that remains in the blood for 18 to 20 hours. how process synthesis analysis of cotinine in the blood????
BalasHapusCotinine is an alkaloid found in tobacco and is also a metabolite of nicotine.[ The word "cotinine" is an anagram of "nicotine". Cotinine is used as a biomarker for exposure to tobacco smoke and has also been sold as an antidepressant under the brand name Scotine.
HapusSimilarly to nicotine, cotinine binds to, activates, and desensitizes neuronal nicotinic acetylcholine receptors, though at much lower potency in comparison. It has demonstrated nootropic and antipsychotic-like effects in scientific research.
Measure of nicotine exposure
Cotinine has an in vivo half-life of approximately 20 hours, and is typically detectable for several days (up to one week) after the use of tobacco. The level of cotinine in the blood is proportionate to the amount of exposure to tobacco smoke, so it is a valuable indicator of tobacco smoke exposure, including secondary (passive) smoke.[8] People who smoke menthol cigarettes may retain cotinine in the blood for a longer period because menthol can compete with enzymatic metabolism of cotinine.[9] Genetic encoding of liver enzymes may also play a role, as people of African descent routinely register higher blood cotinine levels than Caucasians.[10] Several variable factors (such as menthol cigarette preference and puff size) suggest that the explanation for this difference may be more complex than gender or race.[citation needed]
Cotinine levels <10 ng/mL are considered to be consistent with no active smoking. Values of 10 ng/mL to 100 ng/mL are associated with light smoking or moderate passive exposure, and levels above 300 ng/mL are seen in heavy smokers - more than 20 cigarettes a day. In urine, values between 11 ng/mL and 30 ng/mL may be associated with light smoking or passive exposure, and levels in active smokers typically reach 500 ng/mL or more. Cotinine assays provide an objective quantitative measure that is more reliable than smoking histories or counting the number of cigarettes smoked per day. Cotinine also permits the measurement of exposure to second-hand smoke (passive smoking).
Drug tests can detect cotinine in the blood, urine, or saliva.
However, some smoking cessation programs contain Nicotine which will result in a positive for Cotinine presence. Therefore, the presence of Cotinine is not a conclusive indication of tobacco use.PRINCIPLES OF THE COTININE TEST
The Calbiotech Cotinine Blood Test kit is a solid phase competitive ELISA. The samples and Cotinine enzyme conjugate are added to the wells coated with anti-Cotinine antibody. Cotinine in the samples competes with a Cotinine enzyme (HRP) conjugate for binding sites. Unbound Cotinine and Cotinine enzyme conjugate is washed off by washing step. Upon the addition of the substrate, the intensity of color is inversely proportional to the concentration of Cotinine in the samples obtained with the Cotinine blood test. A standard curve is prepared relating color intensity to the concentration of the Cotinine.
http://en.wikipedia.org/wiki/Cotinine
http://www.calbiotech.com/products?page=shop.product_details&flypage=flypage.tpl&product_id=51&category_id=11&keyword=cotinine