The toxicology of cocoa and methylxanthines: a review of the literature.
The critical review of the literature cited on pharmacology, toxicology, metabolism, and safety assessment clearly demonstrates that cocoa per se has not attracted a great deal of scientific interest because of its long-term usage with no reported adverse effects that would be injurious to man. On the other hand, a great deal of research has been directed towards understanding the pharmacological properties of the methylxanthines--caffeine, theobromine, and theophylline. Much of the emphasis on metabolism, toxicology, teratogenic potential, and safety assessment has been on the evaluation of caffeine. In light of the serious health concerns ascribed to the effects of caffeine and the lack of basic information on theobromine and theophylline, it is imperative that a major research program be undertaken to evaluate these methylxanthines and, of course, cocoa, coffee, and tea. It only will be through elucidating their mechanism of action that we will be in a position to assess their safety. Before committing research efforts to evaluating the long-term effects of these methylxanthines and their respective foodstuffs, which serve as our primary source of exposure, it is critical to initiate more basic research on the metabolism of caffeine, theophylline, and theobromine in several animal species and man. While published reports do appear in this area, it is essential to understand fully the similarities and differences between various animals and man. The influence of dietary factors and drug interactions must also be determined. Before establishing dosage levels for a chronic toxicity study, the pharmacokinetics of the dose must be determined in the species that will be used in long-term studies. This is necessary if there is a dose-dependency in the animal above which saturation may occur and the plasma half-life kinetics change, or shifts occur either in the metabolic pathways of degradation and/or in the route of excretion from the body. The area of teratology must also be thoroughly evaluated. Studies undertaken should include identification and quantitation of the metabolites of caffeine, theophylline, and theobromine in the pregnant animal, the respective pharmacokinetics of each compound, dose-dependency (if this is the case), and their potential teratogenicity. In addition, the influence of other drugs or dietary variables must be included. In addition to teratology, a great deal of research is needed to assess and quantitate fetal and neonatal metabolism of these compounds.(ABSTRACT TRUNCATED AT 400 WORDS)
D000818:Animals; D002099:Cacao / Q000633:toxicity*; D002110:Caffeine / Q000493:pharmacokinetics / Q000633:toxicity; D004032:Diet; D005260:Female; D005333:Fetus / Q000187:drug effects; D005348:Fibrocystic Breast Disease / Q000139:chemically induced; D006801:Humans; D009152:Mutagenicity Tests; D010945:Plants, Edible; D012098:Reproduction / Q000187:drug effects; D013805:Theobromine / Q000493:pharmacokinetics / Q000633:toxicity; D013806:Theophylline / Q000493:pharmacokinetics / Q000633:toxicity; D014018:Tissue Distribution; D014970:Xanthines / Q000493:pharmacokinetics / Q000633:toxicity*
D014970:Xanthines; C008514:methylxanthine; D002110:Caffeine; D013806:Theophylline; D013805:Theobromine