The Contribution of cocoa additive to cigarette smoking addiction

RIVM report 650270002 Page 71 of 207
Histamine
Little is known about the profile of the pyrolysis/combustion products of histamine.
Conclusion
The daily intake of histamine from cigarettes (from added cocoa) is about 500 times
less than histamine intake from other sources such as chocolate, wine or Dutch
cheese. Assuming similar bioavailability, the plasma concentration reached after
ingestion of histamine from chocolate sources or other food sources is expected to be
significantly higher, than after exposure from cigarettes. However, the different route
of application via smoking as compared to other sources should be taken into
account. Therefore, the systemic and the local effect of smoking related exposure to
histamine might be a point of concern. Since nothing is known about the
pyrolysis/combustion products of histamine in cigarette smoke, this may be an
additional point of concern.
PHARMACODYNAMICS
Mechanism of action
Histamine is an autacoid that is closely associated with mast cells and functions as a
mediator of inflammation. Like serotonin, it is also a neurotransmitter in the central
and peripheral nervous systems. Its effects are mediated by three receptor subtypes
with differential selectivities for both agonists and antagonists (H1, H2 and H3) (13,
14) They share structural and membrane topography features with other metabotropic
receptors. Histamine receptors H1 and H2 are postsynaptic whereas H3 is presynaptic.
There are no known natural toxins or toxicants of histamine receptors. The H1 and H2
antagonists are potent therapeutics. The potent therapeutic H1 agonists are effective
for the treatment of allergies, but their side effects and toxicities include sedation and
anticholinergic actions. Antagonists for H2 receptor are excellent therapeutics for
peptic and gastric ulcers, because of their ability to block histamine-induced gastric
acid production (15).
Recently a new histamine receptor, H4, was discovered in bone marrow and it may be
a therapeutic target for the regulation of immune function, particularly with respect to
allergy and asthma (16).
H1-receptors have been detected in a wide variety of tissues including: mammalian
brain, smooth muscle from airways, gastrointestinal tract, genito-urinary system,
cardiovascular system, adrenal medulla, endothelial cells and lymphocytes. The
primary mechanism by which histamine H1-receptors produce functional responses in
cells is the activation of phospholipase C. An H1-receptor mediated increase in either
inositol phosphate accumulation or intracellular calcium mobilization has been
described.
Histamine H2-receptors have a potent effect on gastric acid secretion. This receptor
occurs in cardiac tissues, smooth muscle of the airway, uterine and vascular system in
high densities and is widely distributed in the brain. H2-receptors in basophils and
mast cells have been shown to negatively regulate the release of histamine. Histamine
H2-receptors is coupled to the adenylyl cyclase via the GTP-binding protein Gs. H2receptor
mediated effects on cAMP accumulation have been observed in brain cells,
gastric mucosa, cardiac myocytes, vascular smooth muscle and neutrophils.
Histamine H3-receptors have inhibitory effects on the neurotransmitter release in the
CNS and in the periphery. The signal transduction pathway of the H3-receptor is