The Contribution of cocoa additive to cigarette smoking addiction

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Page 54 of 207 RIVM report 650270002 Serotonin chewing of nicotine gum (4-8 mg nicotine) resulted in a transient increase in platelet 5-HT by about 100% in non-smokers, but not in smokers. In conclusion, smoking of cigarettes can cause an increase in platelet serotonin, most likely via enhanced supply of serotonin from enterochromaffin cells, which can be stimulated via nicotine receptors (10). Metabolism Serotonin found in enterochromaffin cells and neurons is synthesized in situ from tryptophan. Tryptophan is first hydroxylated to 5-hyroxytryptophan by enzym tryptophan-5-hydroxylase and is then decarboxylated to serotonin by non-specific aromatic L-amino acid decarboxylase. Serotonin is then taken up into secretory granules and stored. Most of the serotonin, endogenous or ingested, undergoes oxidative deamination by monoamine oxidase to form 5-hydroxyindoleacetaldehyde. This is promptly degraded, mainly by further oxidation, to 5-hydroxyindoleacetic acid (5-HIAA) by aldehyde dehydrogenase; 5-hydroxyindoleacetalhyde is also reduced (by alcohol dehydrogenase) to 5-hydroxytryptophol (5-HTOL). The three enzymes are present in liver and various tissues that contain serotonin, including the brain and the lung (6). Serum serotonin is inactivated by pulmonary and vascular endothelial monoamine oxidase, hepatic inactivation and cellular reuptake. Rapid inactivation of unbound serotonin appears to be an important part of normal serotonergic activity (13, 34). Excretion The principal metabolite, 5-HIAA, is excreted in the urine, along with much smaller amounts of 5-HTOL, mainly as the glucuronide or sulfate. About 2 to 10 mg of 5- HIAA is excreted daily by normal adults as a result of metabolism of endogenous serotonin. Patients with malignant carcinoid (tumor of neuroendocrine cells) excrete larger amounts. Ingestion of ethyl alcohol diverts 5-hydroxyindoleacetaldehyde from the oxidative route to the reductive pathway, because of the elevated concentration of NADH. This greatly increases excretion of 5-HTOL and correspondingly reduces that of 5-HIAA (6). Ingestion of serotonin rich food (banana or walnuts) elevated the excretion of 5-HIAA in the urine. Smoking of 20- 30 cigarettes per day had no influence on the 5-HIAA urinary excretion (3). The pulmonary microvascular endothelium has been shown to be a very important component in the clearance of many circulating bioactive compounds through the pulomonary tissue. It was discovered that serotonin is extensively removed (by about 70%) during a single passage through the lungs of dogs as well as in humans (13). Kinetic parameters An amount of serotonin roughly equal to that present in the body is synthesized each day. Turnover times of serotonin in brain and gastrointestinal tract have been estimated at about 1 and 17 hours, respectively (6).
RIVM report 650270002 Page 55 of 207 Serotonin Critical assessment Serotonin is an endogenous compound, which is distributed throughout the body. It is mainly stored in the enterchromaffin cells (90 %), in the platelets and the CNS. It is synthesized in situ from tryptophan and is metabolised in various tissues. The pulmonary microvascular endothelium has been shown to be very important in the clearance of endogenous serotonin from the plasma; about 70 % serotonin is cleared in a single passage through the lung. Considering the large endogenous serotonin pool (10 mg), it seems unlikely that the low serotonin dose from cigarette smoke (estimated 15 µg/day) will affect the serotonin level in the body. However, the pharamacokinetics on exogenous serotonin, like serotonin inhalation, is not known. Conclusion Only pharmacokinetics data based on endogenous serotonin are known. Conclusions on kinetics from respiratory administration can not be drawn based on the endogenous serotonin kinetics.
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