The Contribution of cocoa additive to cigarette smoking addiction

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Page 20 of 207 RIVM report 650270002 Theobromine In vivo Theobromine has several systemic interaction effects in the body. Based on the low theobromine dose in cigarettes, it is unlikely that these interactions play a role in the health effects of smoking. DEPENDENCY Mechanism of addiction The pharmacology of theobromine in cocoa products has been thoroughly reviewed and the conclusion seems to be that this agent is not responsible for the craving qualities of chocolate (14, 37). Effects of smoking cessation No data available. Critical assessment In the literature, theobromine is not considered as an addictive compound, however it could increase the nicotine availability through bronchodilatation, which subsequently could increase the addictive property of tobacco. Conclusion Theobromine does not seem to play a major role in smoking addiction. COMMERCIAL USE Theobromine is used principally to make caffeine (4). Formerly, theobromine and its derivatives (salts of calcium salicylate (theosalicin), sodium acetate (themisalum) and sodium salicylate (theobromsal)), were used in diuretics, myocardial stimulants, vasodilators and smooth muscle relaxants in both veterinary and human medicine. (1, 2, 4, 8) Now, these applications of theobromine are rather limited. (4, 9) BENEFICIAL EFFECTS Aberrant angiogenesis, the new vessels formation, is a crucial event in the process of tumor growth and expansion. Theobromine significantly suppressed cutaneous neovascular reaction induced in mice by human lung cancer cells (38) and human blood leucocytes and ovarian cancer cells (39). Theobromine also diminished vascular endothelial growth factor (VEGF) (40). These findings suggest that theobromine might be a potent inhibitor of angiogenesis and that its mechanism of action is related to inhibition of VEGF production (40). The antitumor activity of adriamycin was enhanced by combination with theobromine. Theobromine increased the concentration of adriamycin in the tumor without any effects on that in the heart and the liver. The combination of theobromine with adriamycin also significantly increased the inhibition of DNA biosynthesis in the tumor. These findings indicate that the combination of theobromine with adriamycin have no effect on the side effects of adriamycin in the liver and the heart (36). Critical assessment The use of theobromine in human and veterinary medicine for its diuretic, myocardic
RIVM report 650270002 Page 21 of 207 Theobromine and vasodilatory effects is limited. As an inhibitor of angiogenesis and enhancer of antitumor activity of adriamycin it might be of more value in the future. Conclusion In view of cigarette smoking no relevant beneficial effects can be expected. SUMMARY AND FINAL CONCLUSION A source of theobromine in tobacco is cocoa powder, which is used as a flavouring agent. There are no data available on the pyrolysis products of theobromine. Assuming similar systemic and potential effects after oral and inhalation exposure, the additional risk of theobromine by cigarette smoking will be low comparing the low daily intake via cigarettes smoke (estimated to be 4.75 mg/day) with the oral intake via tea drinks, chocolate and cocoa drinks (estimated 138 mg – 864 mg/day). Although oral intake is significantly larger from other sources than from cigarettes, the local effects of theobromine via inhalation on the respiratory system are not studied and might be a point of concern. Theobromine affects the adenosine receptor sites (A1 and A2) and antagonizes the effect of adenosine. Theobromine exerts various pharmacological effects in the body, but these effects are much weaker than those of other methylxanthines, like caffeine and theophylline, and therefore its bronchodilatory capacity is questionable. As other methylxanthines (caffeine) also occur in cigarettes, the combined effect of these methylxanthines on the pulmonary system is not known. After oral intake, theobromine is readily absorbed and widely distributed in tissues, including the brain. Transplacental transport in rats and human was reported and theobromine was identified in fetal rat brain. CYP450 is involved in the metabolism of theobromine. The half-times in serum ranged from 6.1 to 10 h. There are no data on pharmacokinetics in animals and humans from respiratory studies. The acute toxicity of theobromine is low. In humans clinical signs such as sweating, trembling and severe headache are observed at high daily doses (0.8 – 1.5 g theobromine). Animal lethal dose (LD50) for animals range from 300 mg/kg for dogs to 1356 mg/kg for mice. After semichronic treatment of rats with high doses of theobromine (25 – 250 mg/kg) a reduction in body weight and testicular atrophy is observed. Theobromine may have mutagenic properties. There is no evidence that theobromine is carcinogenic. No data on the toxic effects of theobromine administered through inhalation are available. Toxic effects are observed at high oral theobromine doses. It is unlikely that exposure to theobromine through smoking leads to systemic theobromine levels that exert toxicologically relevant effects. Since no data on the toxicological effects of theobromine exposure through inhalation are available, the influence of exposure to theobromine on the respiratory system through smoking cannot be established. Theobromine is able to form stable compounds with bases and unstable compounds with salts. Furthermore it can form complexes. Theobromine shows interaction effects with agonists/antagonists of the adenosine receptors, the liver enzym system and phosphodiesterase. All these in vivo interaction effects are described for other than inhalation route. Whether these interaction effects also occur by intake through
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