The Contribution of cocoa additive to cigarette smoking addiction

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).