Showing papers on "Theobromine published in 1993"
TL;DR: Older men consuming 11 to 20 and over 20 mg of theobromine per day were at increased risk of prostate cancer, while pack-years of cigarettes smoked, alcohol intake, and consumption of alcohol, coffee, tea, and caffeine were not associated with prostate cancer risk.
Abstract: Data from a population-based study of newly diagnosed cases of prostate cancer (n = 362) and age-matched controls (n = 685) conducted in Utah (United States) between 1983 and 1986 were used to determine if cigarette smoking, alcohol, coffee, tea, caffeine, and theobromine were associated with prostate cancer risk. These factors were examined since their use differs in the Utah population, which is comprised predominantly of members of the Church of Jesus Christ of Latter-day Saints (LDS or Mormon), from most other populations. Pack-years of cigarettes smoked, alcohol intake, and consumption of alcohol, coffee, tea, and caffeine were not associated with prostate cancer risk. Compared with men with very low levels of theobromine intake, older men consuming 11 to 20 and over 20 mg of theobromine per day were at increased risk of prostate cancer (odds ratio [OR] for all tumors = 2.06, 95 percent confidence interval [CI] = 1.33-3.20, and OR = 1.47, CI = 0.99-2.19, respectively; OR for aggressive tumors = 1.90, CI = 0.90-3.97, and OR = 1.74, CI = 0.91-3.32, respectively). We present biological mechanisms for a possible association between prostate cancer and theobromine. This finding needs further exploration in studies with a wider range of theobromine exposures and more men with aggressive tumors.
108 citations
TL;DR: Results show that long-term treatment with caffeine in a dose that gives plasma levels of 6-10 microM decreases the effects of NMDA on e.g. seizure susceptibility, and that this effect cannot be ascribed to changes of A1 adenosine receptor density.
97 citations
Journal Article•
TL;DR: In this article, the enzyme kinetics with 7-ethoxyresorufin as substrate resulted in KM values of 0.017 and 1.67 microM and Vmax values of 840 and 387 pmol/mg/min, respectively.
Abstract: Heterologous expression of cytochrome P-450 cDNAs in yeast is a potent instrument for the study of enzyme-specific parameters and can be used to answer questions with regard to substrate specificity as well as drug interaction in a background with no interfering activities. Two cDNAs of human CYP1A1 and CYP1A2 were expressed in yeast Saccharomyces cerevisiae, and microsomes of transformed strains contained substantial amounts of functional heterologous enzymes. Enzyme kinetics with 7-ethoxyresorufin as substrate resulted in KM values of 0.017 and 1.67 microM and Vmax values of 840 and 387 pmol/mg/min for CYP1A1 and CYP1A2, respectively. Both heterologous enzymes showed an overlapping substrate specificity pattern assayed with different phenoxazone ethers and caffeine. Caffeine was shown to be metabolized by CYP1A2 and CYP1A1. Both enzymes formed paraxanthine and minor amounts of theobromine; however, trimethyluric acid was exclusively formed by CYP1A1. The fact that theophylline was not formed by either enzyme anticipates the involvement of additional enzyme(s) in the primary metabolism of caffeine. Inhibition studies with caffeine, phenacetin, 17 beta-estradiol, and progesterone as inhibitors of the CYP1A1 and CYP1A2 catalyzed O-deethylation of 7-ethoxyresorufin suggest all compounds as possible substrates of CYP1A enzymes. 17 beta-estradiol inhibited CYP1A1-catalyzed paraxanthine and trimethyluric acid formation. In contrast 17 beta-estradiol did not inhibit CYP1A2-catalyzed formation of primary caffeine metabolites. These data clearly demonstrate the capacity of human CYP1A1 and CYP1A2 to metabolize caffeine. Furthermore, possible consequences of CYP1A enzyme inhibition by caffeine, phenacetin, 17 beta-estradiol, and progesterone will be discussed.
82 citations
TL;DR: It was found that addition of metal ions such as Zn2+ to intact cells of a caffeine-degrading isolate from soil, Pseudomonas sp.
Abstract: Production of theobromine from caffeine by caffeine-degrading bacteria was studied. We found that addition of metal ions such as Zn2+ to intact cells of a caffeine-degrading isolate from soil, Pseudomonas sp. No.6, resulted in a high theobromine accumulation from caffeine. We hypothesized that Zn2+ acts as a selective inhibitor of one of the theobromine-demethylating enzymes and further screened for theobromine-producing activities in the presence of Zn2+ among a number of caffeine-using microorganisms. A strain identified taxonomically as Pseudomonas putida No. 352 showed the best productivity among 973 microorganisms of stock cultures and soil isolates. Culture conditions for the production of theobromine from caffeine by P. putida No. 352 were studied. Under optimal conditions, nearly 20 g/liter of theobromine was produced from caffeine in a yield of 92%.
69 citations
TL;DR: The fetal rat brain accumulates theophylline, theobromine and paraxanthine when exposed to caffeine doses comparable to those attainable by normal human consumption, and it is suggested that particular attention should be paid to the consumption of caffeine during pregnancy.
40 citations
TL;DR: Pulse-chase experiments and the inhibitory effects of coformycin suggest that the biosynthesis of caffeine from adenine nucleotides is initiated by the reaction catalysed by AMP deaminase, which appears to be operative in both young and mature leaves.
38 citations
TL;DR: A cautionary note is sounded about caffeine intake in pregnancy after a single oral dose of 5 and 25 mg/kg caffeine was administered to 20-day pregnant and non-pregnant rats.
Abstract: 1. The dispositions of caffeine and its immediate dimethylxanthine metabolites, theobromine, theophylline and paraxanthine were studied after a single oral dose of 5 and 25 mg/kg caffeine administered to 20-day pregnant and non-pregnant rats, respectively.2. Peak plasma levels were reached between 1 and 3 h in all fluids and tissues studied.3. The elimination phase, however, differed significantly between the pregnant and non-pregnant groups. For 25 mg/kg the plasma half-life (t1/2) of caffeine was significantly longer in the pregnant than the non-pregnant group; for 5 mg/kg the elimination rate of caffeine was similar in both groups.4. AUC values were used to compare caffeine and metabolite exposure in foetal tissues. At 5 mg/kg, peak concentrations for amniotic fluid, foetal blood, liver and kidney were not significantly different from one another. At 25 mg/kg peak levels in foetal liver and kidney were significantly less than those of foetal blood, amniotic fluid or placenta.5. Because of the observed ...
27 citations
TL;DR: The results indicate that methylxanthines including caffeine may act directly on the glycine receptor Cl− channel complex in rat hippocampal pyramidal neurones and the blockade of the inhibitory amino acid response by methylxAnthines may be involved in the excitatory side effects of methylXanthines in the mammalian central nervous system.
Abstract: 1. The effects of caffeine and related compounds on responses mediated by inhibitory amino acids were investigated in freshly dissociated rat hippocampal pyramidal neurones by conventional and nystatin perforated patch-clamp techniques. 2. Glycine and gamma-aminobutyric acid (GABA) evoked Cl- currents in hippocampal neurones. The half-maximum effective concentrations (EC50) of glycine and GABA were 8.5 x 10(-5) and 5 x 10(-6) M, respectively. 3. Caffeine reversibly inhibited both 10(-4) M glycine- and 10(-5) M GABA-induced Cl-currents in a concentration-dependent manner. The half-maximum inhibitory concentrations (IC50) of caffeine were 4.5 x 10(-4) M for the glycine response and 3.6 x 10(-3) M for the GABA response. 4. Caffeine shifted the concentration-response curve of IGly to the right without affecting the maximum response. 5. The inhibitory action of caffeine did not show voltage-dependency. 6. The blocking action of caffeine was not affected by intracellular perfusion with 5 mM BAPTA or by pretreatment with the protein kinase A inhibitor, H-8. This excludes the participation of Ca2+ or cyclic AMP in the inhibitory action of caffeine. 7. Caffeine failed to inhibit the augmentations of aspartate- and N-methyl-D-aspartate (NMDA) -gated current by glycine, suggesting that caffeine has no effect on the allosteric glycine binding site on the NMDA receptor. 8. The inhibitory effects of some xanthine derivatives on IGly were compared. The inhibitory potency of those compounds on IGly was in the order of pentoxifylline > theophylline > or = caffeine > paraxanthine > IBMX > or = theobromine > dyphylline. Xanthine had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)
26 citations
TL;DR: 1-Propyl-3,7-dimethylxanthine and 1-propargyl-2,4,5,6-dimethyltestosterone (EC50 5 mM) were several-fold more potent than caffeine in causing elevation of [Ca2+]i and the latter was at least as efficacious.
20 citations
TL;DR: Although most of the radioactivity from [8-14C]inosine was recovered as CO2 and ureides, considerable amounts of radioactivity were recovered as purine alkaloids, and synthesis of caffeine from adenine nucleotides seems to be initiated by the reaction of AMP deaminase.
19 citations
01 Aug 1993
TL;DR: The identity of Caffeine as the major Xanthine present in Guarana has been confirmed by Spectroscopic Methods as discussed by the authors by using spectroscopic methods, but the presence of Tetramethylxanthine could not be detected.
Abstract: The Identity Of Caffeine As The Major Xanthine Present In Guarana Has Been Confirmed By Spectroscopic Methods. Theobromine and Theophylline Were Present In Small Amounts But The Presence Of A Tetramethylxanthine Could Not Be Detected. Evidence Was Obtained For The Presence Of A Complex Of Caffeine and A Tannin. Hplc Was Used To Quantify The Caffeine Present In Various Samples Of Guarana and Its Products. The Amount Of Caffeine Present Was Found To Be Between 2.0 and 4.5% W/W Which Is Of The Same Order As That Present In Tea and Coffee.
TL;DR: The results of this study indicate that minor amounts of caffeine and its primary degradation products are excreted via the bile allowing local interference with epithelial cell metabolism of bile ducts and gallbladder.
TL;DR: In this paper, the role of 7-methylxanthine as an intermediary compound in the degradation of theobromine to ranthine in coffee, leaves and immature fruits of Coffea dewevrei were incubated with [8- 3 H]caffeine plus allopurinol.
Abstract: To investigate the role of 7-methylxanthine as an intermediary compound in the degradation of theobromine to ranthine in coffee, leaves and immature fruits of Coffea dewevrei were incubated with [8- 3 H]caffeine plus allopurinol. In vivo inhibition of xanthine degradation occurred in fruits and leaves fed with allopurinol since marked incorporation of radioactivity in xanthine and 7-methylxanthine was observed. Nevertheless, HPLC analysis did not reveal any radioactivity in 7-methylxanthine. The results suggest that in coffee theobromine is degraded to xanthine via 3-methylxanthine and 7-methylxanthine is exclusively involved in the caffeine biosynthesis pathway
TL;DR: Synthesis of theobromine from two separate purine nucleotide pools, one synthesized de novo and one via salvage, added xanthine 5[prime]-monophosphate (XMP), inosine, or hypoxanthine failed to reduce the incorporation of [14C]formate into the Obromine but diluted the specific radioactivity of [ 14C]adenosine and [14 C]adenine incorporated into the obromine.
Abstract: In Coffea arabica leaves, the purine ring of theobromine (3,7-dimethylxanthine) and caffeine (1,3,7-trimethylxanthine) is provided by de novo purine biosynthesis: (a) [14C]glycine, [14C]bicarbonate, and [14C]formate were incorporated into inosine 5[prime]- monophosphate (IMP), sum of adenine nucleotides ([sigma]Ade), theobromine, and caffeine; and (b) incorporation of [14C]formate into IMP, [sigma]Ade, theobromine, and caffeine was inhibited by azaserine, a known inhibitor of de novo purine biosynthesis Capacity of coffee leaves to salvage added purines was demonstrated by incorporation of [14C]hypoxanthine into [sigma]Ade and the incorporation of [14C]adenosine, [14C]adenine, [14C]inosine, and [14C]hypoxanthine into both theobromine and caffeine Consistent with synthesis of theobromine from two separate purine nucleotide pools, one synthesized de novo and one via salvage, added xanthine 5[prime]-monophosphate (XMP), inosine, or hypoxanthine failed to reduce the incorporation of [14C]formate into theobromine but diluted the specific radioactivity of [14C]adenosine and [14C]adenine incorporated into theobromine Evidence that theobromine is not the immediate precursor of caffeine is provided: (a) [14C]xanthine was incorporated into caffeine but not into theobromine; (b) exogenous xanthine diluted the specific radioactivity of caffeine synthesized from [14C]adenine and [14C]hypoxanthine but caused accumulation of radiolabel in theobromine; (c) allopurinol, a known inhibitor of the conversion of hypoxanthine to xanthine, reduced incorporation of [14C]adenine and [14C]hypoxanthine into caffeine but caused accumulation of radiolabel in theobromine; and (d) incorporation of [14C]formate into caffeine, but not into theobromine, was reduced by added XMP, inosine, or hypoxanthine
TL;DR: It is suggested that caffeine and trimethadione metabolism in healthy subjects is mediated by only in part by a form(s) of P450 enzymes involved.
Abstract: Pharmacokinetic interactions between caffeine 2 mg/kg and trimethadione 4 mg/kg were evaluated in 10 healthy volunteers. Whether administered alone or together, the total body clearance (CL), the apparent volume of distribution (Vd) and half-life (t1/2) of caffeine and trimethadione were the same, however, there was a weak correlation between the CL of caffeine and trimethadione [alone: r = 0.51 (P < 0.05); coadministered: r = 0.56 (P < 0.05)]. There were also weak correlations between the CL of trimethadione and the area under the serum concentration-time curves (AUC) of theobromine (r = -0.61, P < 0.05), paraxanthine (r = -0.69, P < 0.05) and theophylline (r = -0.60, P < 0.05), when the two drugs were administered alone. After combined administration, the correlation between the CL of trimethadione and the AUCs of the metabolites of caffeine were as follows: theobromine r = -0.63 (P < 0.05); paraxanthine r = -0.68 (P < 0.05); theophylline r = -0.65 (P < 0.05). These findings suggest that caffeine and trimethadione metabolism in healthy subjects is mediated by only in part by a form(s) of P450 enzymes involved.
TL;DR: It may be concluded that the methylxanthines possess qualitatively different actions on the central serotonergic neuron; caffeine and theophylline appear to have direct effects on the postsynaptic neuron, but theobromine and pentoxifylline do not.
Abstract: Effects of the four methylxanthines (100 mg/kg, IP)—caffeine, theophylline, theobromine, and pentoxifylline—on the central serotonergic neuron were studied in mice using a behavioral model, the head-twitch response. The four methylxanthines potentiated the head twitches induced by 5-hydroxytryptophan (5-HTP) in pargyline-pretreated mice; pentoxifylline was the most potent. The potentiating effect of pentoxifylline was increased by paroxetine, the selective inhibitor of uptake of 5-hydroxytryptamine (5-HT), but those of the other drugs were not. In nontreated animals, caffeine directly induced head-twitch responses, which were not affected by pargyline pretreatment but were increased by prior treatment with 5,7-dihydroxytryptamine (5,7-DHT). The number of head twitches produced by caffeine in 5,7-DHT-treated mice was increased twofold by p -chlorophenylalanine ( p -CPA), the tryptophan hydroxylase inhibitor. In mice treated with both 5,7-DHT and p -CPA, theophylline induced the responses, although much less potently than caffeine. Theobromine and pentoxifylline produced even fewer responses. From the results of the present study, it may be concluded that the methylxanthines possess qualitatively different actions on the central serotonergic neuron; caffeine and theophylline appear to have direct effects on the postsynaptic neuron, but theobromine and pentoxifylline do not.
TL;DR: In this paper, a modified method for a qualitative and quantitative analysis of theophylline in small blood serum volume (40 μl) was developed, where blood serum samples containing theobromine, as internal standard and caffeine from coffee consumption of the patients were centrifuged with acetonitrile to precepitate proteins.
Abstract: A modified method for a qualitative and quantitative analysis of theophylline in small blood serum volume (40 μl) was developed. According to this method, blood serum samples containing theobromine, as internal standard and caffeine from coffee consumption of the patients are centrifuged with acetonitrile to precepitate proteins. These serum samples are evaporated in a water bath at 45°C under stream of nitrogen to remove organic solvents. Then the samples were treated by solid—phase liquid extraction using C18 Bond Elut cartridges preconditioned with methanol and water. The Chromatographic Separation was achieved on a Lichrosorb RP-18 10 μm ODS, 250×4 mm I.D. using methanol: 0.05M ammonium acetate (42:58) at a pH 7.0. The eluted components are detected at 272 nm. The retention time is 3.03 min for theobromine and 3.76 min for theophylline. Theophylline is quantitated by comparing theophylline peak areas with that of known quantities of the internal standard. The peak areas were found to be linea...
Journal Article•
TL;DR: This liver slices model could be used as a simple and versatile model to study metabolism during maturation in rats to find out the main pathways of in vitro caffeine metabolism at all ages.
Abstract: The metabolism of caffeine was investigated in liver slices from newborn, preweanling, postweanling, and adult rats. All metabolites were identified and quantified by HPLC without using radioactive compound. Caffeine metabolism underwent dramatic changes during maturation in rats. The specific activity of the enzyme system was extremely low when liver slices from 1-day and 7-day-old rats were used. This capacity increased gradually with increasing age and reached a peak following weaning at 21 days of age. In rat liver slices, N-1 demethylation to theobromine was the main pathway of in vitro caffeine metabolism at all ages. Theobromine represented 25% of total caffeine metabolites at day 1 and about 40% at all others ages. 1,3,7-6-amino-5-(N-formylmethylamino)-1,3-dimethyluracil is a minor metabolite in newborn (1-day-old), preweanling (7-day-old), and adult rats (120-day-old), but an important metabolite in postweanling rats. Conversely, 1,3,7-trimethyluric acid is a major metabolite in newborn and adult rats and a minor one in preweanling and postweanling rats. This liver slices model could be used as a simple and versatile model to study metabolism during maturation.
TL;DR: Pregnandiol is a potent inhibitor of microsomal drug metabolism, specifically of cytochrome P450 IA, which could explain the immaturity of some metabolic pathways of caffeine in neonates, consistent with the hypothesis that C-8 hydroxylation and demethylation of caffeine are mediated by different isoenzymes.
Abstract: Three groups of six 5-week-old Sprague Dawley female rats received i.p. injections of pregnandiol, 1.25, 2.50 or 5 mg/kg, respectively, in triolein daily for 7 days. Caffeine metabolism was studied in liver slices on day 8 by HPLC. Only primary metabolites were formed. N-1 demethylation was the most important pathway (theobromine represented 51% of total dimethylxanthines). Unlike in human in vitro or in vivo, 1,3,7-DAU (6-amino-5-(N-formylmethylamino)-1,3-dimethyluracil) was an important metabolite (9.7% of total caffeine metabolites). Pregnandiol inhibited N-1, N-3 and N-7 demethylation in vitro (-33%, -33% and -28%, respectively, at 5 mg/kg/day), but it had no effect on N-1 demethylation at 1.25 or 2.50 mg/kg/day. Pregnandiol at all doses had no effect on 1,3,7-trimethyluric acid and 1,3,7-DAU formation. These results are consistent with the hypothesis that C-8 hydroxylation and demethylation of caffeine are mediated by different isoenzymes. They indicate that pregnandiol is a potent inhibitor of microsomal drug metabolism, specifically of cytochrome P450 IA, which could explain the immaturity of some metabolic pathways of caffeine in neonates.
Journal Article•
TL;DR: Caffeine was investigated in human cancer cells which were clinically known to be radioincurable and found that hepatocellular carcinoma whilst less radiosensitive than colon adenocarcinoma was 4 times more susceptible to caffeine.
Abstract: The effect of caffeine, the methylated xanthine, in sensitizing the lethal action of ionizing radiation in vitro was investigated in human cancer cells which were clinically known to be radioincurable. The tumor lines were hepatocellular carcinoma and colon adenocarcinoma. Plateau phase cultures, after absorbing doses of 2 Gy, survived at a rate of 56.30 per cent for colon cancer and at 66.05 per cent for liver cancer. Both lines were radiosensitized by caffeine but at different potencies. Noteworthily, hepatocellular carcinoma whilst less radiosensitive than colon adenocarcinoma was 4 times more susceptible to caffeine. The lowest effective caffeine concentration for liver cancer was 2 mM which slightly exceeded the anticipated lethal concentration in humans. Research on radiosensitizing effect of methylated xanthines on hepatoma system still remains intriguing. Future work should be pursued with the use of less toxic compounds, such as theobromine.
Journal Article•
TL;DR: Tołpa Peat Preparation administered in various doses does not influence the ability of mononuclear cells obtained from diabetic patients with proliferative retinopathy to induce neovascularization response in H-LIA test and methylxanthines significantly decrease the angiogenic activity of these cells.
Abstract: Tolpa Peat Preparation (TPP) administered in various doses does not influence the ability of mononuclear cells (MNC) obtained from diabetic patients with proliferative retinopathy to induce neovascularization response in H-LIA test. Methylxanthines (theophylline, theobromine) significantly decrease the angiogenic activity of these cells. The therapeutic value of these drugs in proliferative retinopathy should be evaluated.
TL;DR: Theobromine increases exercise performance by reducing glycogen use and enhancing free fatty acid availability to the working muscle in untrained rats.
Abstract: Theobromine ingestion (100 mg/kg body weight) did not affect resting plasma fatty acid concentration in untrained rats, whereas fatty acid concentration was higher (p ≤0.001) following exhaustive treadmill exercise in the theobromine group (0.67 ± 0.08 mM, mean ± SEM) than in the controls (0.31 ± 0.10 mM). Run time to exhaustion was also greater (p ≤0.02) for the theobromine rats (44.0 ± 6.9 min) compared with control animals (27.5 ± 3.5 min). Liver glycogen utilization rate was lower (p ≤0.05) for the theobromine animals than the controls (4.58 ± 0.46 vs. 6.75 ± 0.92 μmol/g/min, respectively), as was soleus muscle glycogen use (p ≤0.03; 0.40 ± 0.04 vs. 0.53 ± 0.04 μmol/g/min, respectively). This suggests that theobromine increases exercise performance by reducing glycogen use and enhancing free fatty acid availability to the working muscle.
Patent•
03 Dec 1993
TL;DR: Theophylline, theobromine and derivatives and salts thereof are used for the chronic prophylactic treatment of mild asthma as mentioned in this paper, the preferred dosage is 100 - 400 mg per day giving a blood plasma level of 1 - 9 mg/L.
Abstract: Theophylline, theobromine and derivatives and salts thereof are used for the chronic prophylactic treatment of mild asthma. The preferred dosage is 100 - 400 mg per day giving a blood plasma level of 1 - 9 mg/L.