The Contribution of cocoa additive to cigarette smoking addiction

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Page 18 of 207 RIVM report 650270002 Theobromine Critical assessment The acute toxicity of theobromine is low. In humans clinical signs such as sweating, trembling and severe headache are observed at high daily doses. After semichronic treatment of rats with high doses of theobromine 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 effects of theobromine administered through inhalation are available. Conclusion Toxic effects of theobromine appear to be found at high 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 through smoking on the respiratory system cannot be established. INTERACTIONS Chemical Forms salts which are decomposed by water, and compounds with bases which are more stable. (2, 4) Theobromine formed 1:1 complexes with the local anesthetic lidocaine (lignocaine) (27). In vivo Theobromine plasma clearance (Cl-TB) was increased in smokers after pretreatment with cimetidine (1 g/day) and sulfinpyrazone (800 mg/day) due to induction of all metabolic pathways (3-demethylation, 7-demethylation, and formation of 6-amino-5- (N-methylformylamino)-1-methyluracil (AMMU)). Cimetidine pretreatment inhibited theobromine 3-demethylation and AMMU formation resulting in a 27 % decrease in Cl-TB in the combined smoker/nonsmoker group. Sulfinpyrazone pretreatment increased Cl-TB by 50 % in the whole group by approximately equal induction of each metabolic pathway. In addition, since AMMU formation was inhibited by cimetidine and induced by cigarette smoking and sulfinpyrazone, it would appear that the conversion of theobromine to AMMU is also mediated by cytochrome P-450 (28). The four primary metabolites of caffeine , 1,3-dimethylxanthine (theophylline), 3,7dimethylxanthine (theobromine), 1,7-dimethylxanthine (paraxanthine), and 1,3,7trimethyluric acid were effective and virtually complete antagonists of acetaminophen (ACM)-induced hepatotoxicity when given immediately after ACM, as were the secondary metabolites, 1-methylxanthine and 1,3-dimethyluric acid. It is suggested that caffeine and its primary metabolites compete with ACM for biotransformation by the cytochrome P-450 mixed function oxidase system, thereby reducing the rate of formation of the hepatotoxic ACM metabolite (29). The ingestion of theobromine in combination with ephedrine improves cold tolerance by increasing heat production, mainly from a greater lipid utilization (30). Adaptation of the human tongue to methylxanthines at concentrations ranging from 10 -5 mol/L to 10 -2 mol/L was found to potentiate taste. Theobromine could potentiate the artificial sweetener acesulfam (31).
RIVM report 650270002 Page 19 of 207 Theobromine The in vivo effects of methylxanthines on 2',5'-oligoadenylate (2,5An) synthetase activity, an interferon-inducible enzyme, were investigated in rat liver nuclei. Theobromine given at 80 mg/kg sc twice daily for 5 d resulted in a 60 % reduction of 2,5An synthetase activity in liver nuclei. Nuclear 2'-phosphodiesterase activity, which catalyzes the degradation of 2,5An, remained low and unchanged following the drug treatments. These results suggest that methylxanthines may interact with interferonmediated actions. The reason for the inhibitory effect of methylxanthines on the basal but not on the induced 2,5An synthetase is unclear (32). The renal effects of xanthines were studied in vitro in the isolated perfused rat kidney (IPRK) and cultured opossum kidney (OK) cells, a continuous cell line that resembles proximal tubule and responds to parathyroid hormone (PTH). A 1 –nmol/L bolus of PTH elevated urinary and perfusate cAMP 50- and 10-fold, respectively OK cells produced a 2-fold cAMP response to 10 nmol/L PTH alone. The rank order of potency at 50 µmol/L to augment OK cell cAMP with 10 nmol/L PTH was (DPX )1,3-Diethyl-8-phenylxanthine> 1,3-dipropyl-8-cyclopentylxanthine (DPC) > 1methyl-3-isobutylxanthine > theobromine > theophylline > caffeine. These studies demonstrate a direct tubular effect of the xanthines. Inhibiton of renal proximal tubular cell phosphodiesterase may explain some effects (e.g., diuresis) of xanthines on renal function (33). The effect of acutely administered adenosine and adenosine analogs on methylxanthine-induced hypercalciuria was concurrently investigated. When rats were fed theobromine urinary Ca 2+ excretion increased; on day 7 values were increased over controls by 54 %. On day 20, an injection of adenosine reduced Ca 2+ excretion in methylxanthine-treated rats to levels not different from control values (34). Theobromine (25-100 mg/kg) significantly reduced the duration of the ethanolinduced behavioral sleep, although not in a dose dependent manner. The most effective reduction of ethanol-induced behavioral sleep was in experimental groups which received 100 mg/kg theobromine (35 %) (35). The antitumor activity of adriamycin (ADR) was enhanced by combination with theobromine or pentoxifylline, without enhancing the side effects of this drug (36). Critical assessment Chemical Theobromine has the potential for complexation and salt formation. In vivo Theobromine shows interaction effects with agonists/antagonists of the adenosine receptors, the liver enzym system and phosphodiesterase. Taking into account the low theobromine dose in cigarettes it is unlikely that significant interactions will occur. Conclusion Chemical Theobromine is able to form compounds with several chemicals.
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