Disease relevance of theobromine

• In the presence of 100 micrograms of caffeine per ml or 200 micrograms of theobromine per ml, sporulation of Clostridium perfringens NCTC 8679 rose from less than 1 to 80 or 85% [1].
• Dietary influences on theobromine-induced toxicity in rats [2].
• We present biological mechanisms for a possible association between prostate cancer and theobromine [3].
• At the maximum tolerated concentration theobromine increased the frequency of TK-/- mutants in mouse lymphoma L5178Y cells [4].
• Theobromine (1.0-2.5 mM) induced contractures in ileal muscle and enhanced both the phasic and tonic components of K-induced contractures in vas deferens and bladder muscle strips [5].

Psychiatry related information on theobromine

• Caffeine and its first-stage metabolites (paraxanthine, theophylline and theobromine) caused a significant potentiation of the locomotor activity induced by bromocriptine, 5 mg/kg, in mice pretreated with reserpine, 5 mg/kg (4h prior to the start of motor activity recordings) [6].

High impact information on theobromine

• Conversely, blocking the cell cycle with vinblastine (G2/M block) or theobromine (mid-G1 block) inhibited the initiation of differentiation by 1,25(OH)2D3 [7].
• The Gr66a mutant exhibited normal tastant-induced action potentials upon presentation of theobromine, a methylxanthine in cocoa [8].
• 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 [9].
• RESULTS: There were marked individual variations in CYP1A2 [(1,7-dimethylurate + paraxanthine)/caffeine], FMO (theobromine/caffeine), and xanthine oxidase (1-methylurate/1-methylxanthine) activities (14-, 42-, and 9-fold, respectively) [10].
• Ratios of serum clozapine N-oxide over clozapine and of urine theobromine versus paraxanthine were used as in vivo indicators of FMO3 activity [11].

Chemical compound and disease context of theobromine

• Theophylline failed to stimulate locomotor activity in the C57BL/6J strain and theobromine failed to stimulate activity in all of the strains tested [12].
• In contrast to the specific antagonism, theobromine blocked the hypothermia induced by both of these adenosine analogs [13].
• The effects of theobromine, a xanthine derivative, on the testis were compared between rats dosed for 2 and 4 weeks to determine whether a 2-week dosing period is long enough to detect toxicity [14].
• The drug pentoxifylline (PTX) (1-(5'-oxohexyl) 3,7-dimethylxanthine) down-regulates human immunodeficiency virus (HIV-1) long terminal repeat (LTR)-directed gene expression in the human monocytic cell line U38 [15].
• Moreover, caffeine and theobromine did not enhance the side toxicity of doxorubicin on the lipid peroxide level, DNA biosynthesis and the doxorubicin concentrations in normal tissues [16].

Biological context of theobromine

• Theobromine kinetics and metabolic disposition [17].
• Relative bioavailability of theobromine in chocolate was 80% that of theobromine in solution [18].
• The metabolic profile of caffeine biotransformation by CYP1A2 averaged 81.5% for paraxanthine, 10.8% for theobromine and 5.4% for theophylline formation [19].
• However, only the primary metabolites were formed through oxidative N-demethylation giving theophylline, paraxanthine and theobromine and, through C-8 hydroxylation, giving 1,3,7-trimethyluric acid and a ring-opened compound the 6-amino-5[N-formylmethylamino]1,3-dimethyl uracil [20].
• Theobromine was also positive in the micronucleus test at 2 X 40 mg/animal and negative in the chromosome aberration test at 1 X 40 mg/animal [21].

Anatomical context of theobromine

• Certain of these cyclic homologues of caffeine, theophylline, theobromine, 3-isobutyl-1-methylxanthine, and enprofylline were inhibitors of binding of adenosine analogues to rat brain A1 and A2 adenosine receptors and were antagonists of A2 adenosine receptors stimulatory to adenylate cyclase in rat PC12 cell membranes [22].
• Pentoxifylline (PFN), analog of theobromine, which phenotypically and functionally alters various cell types including dermal fibroblasts, has been reported to inhibit tumor necrosis factor-alpha (TNF alpha) activation of neutrophils [23].
• Breast milk distribution of theobromine from chocolate [24].
• Pentoxifylline, an analogue of the methylxanthine theobromine, inhibits the proliferation and certain biosynthetic activities of fibroblasts derived from normal human skin [25].
• Studies in vitro indicated that 3,7DMU was the major theobromine metabolite produced by liver microsomes [26].

Associations of theobromine with other chemical compounds

• Normal male volunteers on xanthine-restricted diets had a plasma theobromine (TB) half-life (t1/2) of 6.1 +/- 0.7 hr (mean +/- SEM), a TB metabolic clearance rate (MCR) of 113.8 +/- 6.8 ml/min (mean +/- SEM), and an apparent volume of distribution (aVd) of 59.9 +/- 7.8 L (mean +/- SEM) after a single oral dose of 6 mg/kg of TB [27].
• Modified micellar electrokinetic chromatography (MEKC) analysis of monomeric flavanols (catechin and epicatechin) and methylxanthines (caffeine and theobromine) in chocolate and cocoa was performed by using sodium dodecyl sulfate (SDS) as a principal component of the running buffer [28].
• The effect of caffeine, theophylline and theobromine on acetaminophen-induced hepatotoxicity was evaluated in uninduced, 3-methylcholanthrene- and phenobarbital-induced adult male Sprague-Dawley rats [29].
• The effects of chlordiazepoxide (CDAP) on suppressed behavior of squirrel monkeys were determined alone and in combination with selected methylxanthines (caffeine, theophylline, 8-phenyltheophylline, theobromine, 3-isobutyl-1-methylxanthine) and analogs of adenosine (L-PIA, N6-cyclohexyladenosine, NECA) [30].
• The kinetics of formation of primary metabolites of caffeine (paraxanthine, theophylline, theobromine and 1,3,7-trimethyluric acid) was studied in control (CO) and 3-methylcholanthrene-induced (MC) rat liver microsomes [31].

Gene context of theobromine

• In in vivo and in vitro cultures theobromine diminished vascular endothelial growth factor (VEGF) production [32].
• Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYP1A2 and CYP2E1 [19].
• Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism [33].
• HCV-29-v-raf transfectants do not display transcripts of PAI, in the presence or the absence of theobromine [34].
• Theobromine suppressed angiogenesis induced in mice by HCV-29-v-raf cells, inhibited VEGF mRNA expression, and had no effect on transcription of uPA and tPA in these cells [34].

Analytical, diagnostic and therapeutic context of theobromine

• Identification and quantitation of metabolites in plasma and urine both by HPLC and by thin-layer chromatography coupled with radiography indicated that theobromine was predominant in plasma [17].
• The corresponding figures for interday precision (n = 4 days) were fair (16.1%) in comparison to those obtained with MECC, for which the RSD was 1.49% when theobromine was used as internal standard [35].
• Samples of plasma, saliva, and breast milk were assayed for theobromine by high pressure liquid chromatography [24].
• We report the isolation of a bifunctional coffee caffeine synthase (CCS1) clone from coffee endosperm by reverse transcription-polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE) technique using previously reported sequence information for theobromine synthases (CTSs) [36].
• Biotransformation of theobromine (TBR) was compared in rats, mice, hamsters, rabbits, and dogs by assaying urinary metabolites using HPLC after oral administration of a 5 mg/kg dose containing 8-14C-TBR [37].

References