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At least 19 recordsLinked to original sources
PubMed1975

Biosynthesis of caffeine by tea-leaf extracts. Enzymic formation of theobromine from 7-methylxanthine and of caffeine from theobromine.

1. Extracts prepared from tea leaves with Polyclar AT (insoluble polyvinylpyrrolidine) contained two methyltransferase activities catalysing the transfer of methyl groups from S-adenosylmethionine to 7-methylxanthine, producing theobromine, and to theobromine, producing caffeine. 2. The methyltransferases exhibited the same pH optimum (8.4) and a similar pattern of effects by metal ions, thiol inhibitors and metal-chelating reagents, both for theobromine and caffeine synthesis. Mg2+, Mn2+ and Ca2+ slightly stimulated enzyme activity but they were not essential. Paraxanthine was shown to be most active among methylxanthines, as the methyl acceptor. However, the formation of paraxanthine from 1-methylxanthine was very low and that from 7-methylxanthine was nil, suggesting that the synthesis of caffeine from paraxanthine is of little importance in intact plants. Xanthine, xanthosine, XMP and hypoxanthine were all inactive as methyl acceptors, whereas [2(-14)C]xanthine and [8(-14)C]hypoxanthine were catabolized to allantoin and urea by tea-leaf extracts. The apparent Km values are as follows: 7-methylxanthine, 1.0 times 10(-14)M; theobromine, 1.0 times 10(-3)M; paraxanthine, 0.2 times 10(-3)M; S-adenosylmethionine, 0.25 times 10(-4)M (with each of the three substrates). 3. The results suggest that the pathway for caffeine biosynthesis is as follows: 7-methylxanthine leads to theobromine leads to caffeine. In contrast, it is suggested that theophylline is synthesized from 1-methylxanthine. The methyl groups of the purine ring of caffeine are all derived directly from the methyl group of S-adenosylmethionine. Little is known about the pathways leading to the formation of 7-methylxanthine. 4. A good correlation between caffeine synthesis and shoot formation or growth of tea seedlings was shown, suggesting that the methylating systems in caffeine synthesis are closely associated with purine nucleotide and nucleic acid metabolism in tea plants.

Caffeine↗
PubMed1985

High levels of methylxanthines in chocolate do not alter theobromine disposition.

Theobromine disposition was measured twice in 12 normal men, once after 14 days of abstention from all methylxanthines and once after 1 week of theobromine (6 mg/kg/day) in the form of dark chocolate. Mean theobromine t 1/2, apparent volume of distribution, and clearance after abstinence from all methylxanthines were 10.0 hours, 0.76 L/kg, and 0.88 ml/min/kg. High daily doses of chocolate for 1 week did not change these values. After subjects abstained from methylxanthines, urinary radioactivity over 72 hours after a single, oral dose of [8-14C]theobromine consisted of 42% 7-methylxanthine, 20% 3-methylxanthine, 18% theobromine, 10% 7-methyluric acid, and 10% 6-amino-5[N-methylformylamino]-1-methyluracil. A week of daily theobromine consumption in the form of dark chocolate also did not alter this urinary profile of theobromine and its metabolites. Although these results might appear to differ from other reports of inhibition of theobromine elimination after five consecutive daily doses of theobromine in aqueous suspensions, both the rate and extent of absorption of theobromine in chocolate were less than that of theobromine in solution. Relative bioavailability of theobromine in chocolate was 80% that of theobromine in solution. This reinforces the fundamental principle that both the metabolic and the therapeutic consequences of a particular chemical can differ when that chemical is given in the pure compared with the dietary form.

Administration, Oral↗
PubMed1993

Separate de Novo and Salvage Purine Pools Are Involved in the Biosynthesis of Theobromine but Not Caffeine in Leaves of Coffea arabica L.

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.

Journal Article↗
PubMed1992

Behavioral effects of cocoa and its main active compound theobromine: evaluation by ambulatory activity and discrete avoidance in mice.

Effects of cocoa and its main CNS active constituent methylxanthine theobromine as well as caffeine were evaluated by ambulatory activity, and discrete lever-press and shuttle avoidance in mice. Cocoa (1 g/kg p.o.) and theobromine (10 mg/kg p.o.) significantly increased ambulatory activity. However, the other doses of cocoa and theobromine had no effect on the ambulatory activity. Caffeine increased ambulatory activity with the maximum action at 30 mg/kg p.o. Furthermore, cocoa (0.1, 0.3 and 1 g/kg), theobromine (3, 10, 30 and 100 mg/kg) and caffeine (3, 10, 30 and 100 mg/kg) enhanced the ambulation-increasing effect of methamphetamine (2 mg/kg s.c.). The ambulation-increasing effect of cocaine (20 mg/kg s.c.) was also enhanced by cocoa (1 g/kg), theobromine (10, 30 and 100 mg/kg) and caffeine (10, 30 and 100 mg/kg). On the other hand, comparatively higher doses of theobromine and caffeine disrupted the well established avoidance response. Thus, the avoidance rate was significantly decreased by theobromine (100 mg/kg and more) and caffeine (30 mg/kg and more) under the lever-press situation, and by theobromine (100 mg/kg and more) and caffeine (100 mg/kg) under the shuttle situation. These dose effect relationships revealed that cocoa contains about 1% theobromine. The present results indicate that we may receive the CNS action of theobromine through consumption of theobromine-containing foodstuffs or beverages in our every day life.

Animals↗
PubMed1990

The excretion of theobromine in Thoroughbred racehorses after feeding compounded cubes containing cocoa husk--establishment of a threshold value in horse urine.

Thoroughbred geldings were fed racehorse cubes containing a predetermined concentration of theobromine in the form of cocoa husk. They were offered 7 kg of cubes per day, divided between morning and evening feed, and food consumption was monitored. Urinary concentrations of theobromine were determined following the consumption of cubes containing 11.5, 6.6, 2.0 and 1.2 mg per kg of theobromine, to verify whether or not such concentrations would produce positive urine tests. Pre-dose urine samples were collected to verify the absence of theobromine before each experiment. It became apparent from the results of the first three administrations that the limit of detection of theobromine, using such procedures, would be reached at a feed level of about 1 mg per kg theobromine. Therefore the final administration, using cubes containing 1.2 mg per kg theobromine, was singled out for additional analytical work and quantitative procedures were developed to measure urinary concentrations of theobromine. It was anticipated that the results would form a basis for discussions relating to the establishment of a threshold value for theobromine in horse urine. The Stewards of the Jockey Club subsequently gave notice that they had established a threshold level for theobromine in urine of 2 micrograms/ml.

Animal Feed↗
PubMed1994

Theobromine toxicity on Sertoli cells and comparison with cocoa extract in male rats.

The target cell(s) of theobromine toxicity on rat testes and reproductive toxicity induced by pure theobromine and cocoa extract are evaluated in the present studies. Theobromine (500 mg/kg x 7 days) inhibited body weight gain in treated rats. Decreased cauda epididymal sperm reserve (38%), seminiferous tubule fluid (STF) volume (33%), lactate concentration in STF (22%), inhibition of binding activity of androgen binding protein (ABP, 21%) and reduced ABP content in STF were also observed in theobromine-treated animals. Cocoa extract containing an equivalent amount of theobromine did not produce significant toxicity in treated rats. Theobromine concentrations in serum and testes from pure theobromine-treated rats were 1.8- and 1.6-fold higher, respectively, than that in rats treated with cocoa extract. The results support Sertoli cells as the primary target cells of theobromine toxicity. The lower theobromine concentrations in serum and testes of cocoa extract-treated rats could account for the lower toxicity in these animals.

Animals↗
PubMedDate not supplied

Comparison of theophylline and theobromine metabolism in man.

The total plasma and partial metabolic and renal clearances of theobromine and theophylline were determined in 13 healthy volunteers. Total plasma clearance for theobromine was 46% greater than that for theophylline, but the unbound clearances were almost identical. Theobromine renal clearance was 67% greater than that for theophylline but most of the difference was due to the lower protein binding of theobromine (free fraction = 0.86 compared to 0.58 for theophylline). Clearance by N-demethylation at the 3-position was 3.7-fold higher (unbound clearance 2.5-fold higher) for theobromine than for theophylline, showing that the position of the other methyl substituent (positions 1 or 7) is a major determinant of metabolic rate. There was a high degree of correlation between theophylline and theobromine plasma clearances (r = 0.86) and also between partial metabolic clearances both within drugs and across drugs (r = 0.65-0.99). The renal clearances of theophylline and theobromine were also correlated (r = 0.71). The results support the view that theophylline and theobromine are metabolized by a common group of cytochromes P-450 under similar regulatory control. Theobromine is a good model compound for assessing the activity of these enzymes in man as it has low pharmacological activity and low protein binding, its total and partial metabolic clearances correlate closely with those of theophylline, and close to 100% of the dose can be recovered as known metabolites.

Adult↗
PubMedDate not supplied

In vivo and in vitro biotransformation of theobromine by phenobarbital- and 3-methylcholanthrene-inducible cytochrome P-450 monooxygenases in rat liver. Role of thiol compounds.

A new in vitro method was developed and applied to establish the role of the hepatic cytochrome P-450 monooxygenases in theobromine biotransformation by control and phenobarbital (PB)- and 3-methylcholanthrene (3MC)-induced Sprague-Dawley rats. In vivo theobromine metabolite formation and pharmacokinetic parameters were also determined to serve as a comparison for in vitro studies. In vivo, the major urinary metabolite was 6-amino-5-[N-methylformylamino]-1-methyluracil (3,7DAU) with lesser amounts of 3,7-dimethyluric acid (3,7DMU), 3-methylxanthine, 7-methylxanthine, 7-methyluric acid, and traces of dimethylallantoin (DMA). Following induction with 3MC, but not PB, selective increases occurred in the urinary excretion of 3,7DAU, indicating that a 3MC-inducible cytochrome P-450 isozyme plays a significant role in this metabolic pathway. Both PB and 3MC induction increased slightly urinary elimination of DMA, a minor metabolite. Pharmacokinetic studies after a single oral dose of 5 mg/kg theobromine revealed a marked effect of 3MC treatment on theobromine elimination, as evidenced by a 59% decrease in theobromine t1/2, a 75% decrease in AUC, and a 284% increase in clearance. By contrast, PB had no effect. Fecal 14C elimination accounted for approximately 5% of the administered theobromine dose, and biliary excretion studies revealed the presence of 3,7DMU, DMA, 3,7DAU, and unchanged theobromine. Studies in vitro indicated that 3,7DMU was the major theobromine metabolite produced by liver microsomes. Conversion rates in PB- and 3MC-induced rats were 2- and 11-fold higher, respectively, than in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Differential antagonism of the behavioral depressant and hypothermic effects of 5'-(N-ethylcarboxamide) adenosine by theobromine.

The methylxanthine, theobromine (3,7-dimethylxanthine), was tested in mice, to determine whether theobromine could function in vivo as an adenosine receptor antagonist, in keeping with its reported in vitro effects as a blocker of agonist binding to the adenosine A-1 receptor. Theobromine doses, which themselves had no direct effects on spontaneous locomotor activity, completely blocked N6-cyclohexyladenosine-induced suppression of locomotor activity but were without effect on 5'-N-ethylcarboxamide adenosine (NECA)-induced decreases in motor activity. In contrast to the specific antagonism, theobromine blocked the hypothermia induced by both of these adenosine analogs. These results demonstrate that theobromine is an active in vivo adenosine receptor antagonist and that the antagonism of N6-cyclohexyladenosine sensitive systems occurs even though theobromine does not stimulate spontaneous locomotor activity. Thus, the behavioral stimulant effects of methylxanthines may be more related to effects on NECA-sensitive systems, which are not blocked by theobromine. The use of in vivo differences in the effects xanthine may provide a useful tool in the development of compounds to probe the mechanisms of caffeine induced CNS effects.

Adenosine↗
PubMed1992

Reproductive toxicity of theobromine and cocoa extract in male rats.

The toxicities of theobromine and cocoa extract on the reproductive tract of male rats were compared in the present study. A cocoa powder extract containing 117 mg theobromine/g extract was prepared using 85% boiling methanol. Sprague-Dawley rats were weighed and dosed daily for 31 days with vehicle, 250 mg/kg theobromine, 2.14 g/kg cocoa extract (117 mg theobromine/g extract), or 0.43 g/kg cocoa extract by oral gavage. The animals were sacrificed on day 32. One testis and epididymis were removed and weighed. The epididymis was saved for the determination of epididymal sperm reserves. The remaining testis was fixed by whole body glutaraldehyde perfusion and processed for morphologic examination. A decrease in body weight gain and epididymal weights were observed in theobromine and high-dose cocoa-extract-treated groups. Theobromine and high-dose cocoa extract caused vacuolation within the Sertoli cell, abnormally shaped spermatids, and failed release of late spermatids in treated animals. Most of the vacuolations were found in the earlier and middle stage seminiferous tubules (stages I to VIII). However, the frequency of some parameters of testis alterations were significantly lower in the high-dose cocoa-extract-treated group compared to the theobromine-treated group. These data demonstrate the ability of a cocoa extract containing theobromine to alter testis structure in a similar pattern but with reduced intensity compared to that observed after oral exposure to pure theobromine.

Animals↗
PubMed1977

Breast milk distribution of theobromine from chocolate.

Six nursing mothers ingested 113 gm of Hershey's milk chocolate containing 240 mg of theobromine. Samples of plasma, saliva, and breast milk were assayed for theobromine by high pressure liquid chromatography. Peak theobromine concentrations of 3.7 to 8.2 mg/l were found in all fluids at 2 to 3 hour after ingestion of chocolate. The disposition half-life of theobromine averaged 7.1 +/- 2.1 hours, body clearance was 65 +/- 20 ml/hour/kilogram, and the apparent volume of distribution was 0.62 +/- 0.13 l/lk. Theobromine is only slightly bound to plasma and milk proteins and concentrations in milk and saliva matched plasma data closely. The mean concentration ratios were 0.82 +/- 0.17 for milk/plasma and 0.92 +/- 0.17 for saliva/plasma. If a mother ate a 4-ounce chocolate bar every 6 hours and the infant nursed when the theobromine concentration in milk was at its peak, the infant could ingest about 10 mg of theobromine per day.

Adult↗
PubMed2004

Multiple effects of theobromine on fetus development and postnatal status of the immune system.

Caffeine and its active derivative, theobromine, are probably the most frequently ingested pharmacologically active substances. Considering their uninhibited transport via the placental barrier as well as immature enzymatic activities and metabolic pathways in embryos and infants resulting in the longer half-life of methyloxanthines and their accumulation, unrestrained uptake of these substances might result in noticeably more pronounced biological effects during pregnancy and the postnatal period. Our previous studies have shown that methyloxanthines are significant inhibitors of angiogenic growth factors production and angiogenesis itself. We have hypothesized that increased uptake of these substances might affect embryonal angiogenesis and, later in the postnatal period, maturation and functional activity of the offspring's immune system. The study was performed on 2-month-old Balb/c mice fed theobromine 2 or 6 mg/day during pregnancy and lactation. On day 18 of pregnancy the number and weight of embryos were assessed as was their tissue angiogenic activity, using the cutaneous angiogenesis assay. In the group of 4-week-old sucklings, body and spleen were weighed together with the trunk, and tail and limb length were measured. Six weeks after birth the splenocytes' mitogen-induced activity and their ability to induce graft-versus-host reaction as well as the humoral response to SRBC antigen were evaluated. Content of theobromine in the embryos' tissue was estimated by high liquid performance chromatography (HPLC). Theobromine feeding resulted in significant inhibition of embryo growth as assessed by their weight and decreased angiogenic activity of their tissue. The theobromine content in embryo tissue from treated groups was higher than in the controls, and the difference was close to significant. In the postnatal period the discrepancies in the treated 4-week-old group's development were also observed in the significantly shorter limbs in comparison to the controls. Moreover in the treated group of 6-week-old sucklings, considerable variations in the immune system's functional activity were registered as far as cellular and immune response were concerned. Respectively, the splenocytes' mitogen-induced proliferative activity was significantly suppressed while the graft-versus-host reaction was up-regulated, and the serum antibodies titer was elevated in correspondence to the observed spleen enlargement. We concluded that a theobromine-enriched diet affects progeny development in both prenatal and postnatal periods. Consequently, particular attention should be paid to the reduction of theobromine consumption, and most probably that of other methyloxanthines, during pregnancy and lactation.

Angiogenesis Inhibitors↗