Disease relevance of p-Xanthine

• CONCLUSIONS: Only extremely high serum paraxanthine concentrations are associated with spontaneous abortion [1].
• CMRs were affected by liver disease (e.g., ratio characterizing paraxanthine demethylation [AAMU + 1X + 1U/17U], control median, 8.3; cirrhosis median, 6.2; p = 0.005) [2].
• In adjusted analyses including paraxanthine and caffeine, serum paraxanthine levels in the highest quartile were associated with increased risk of IUGR (adjusted odds ratio=3.29, 95% confidence interval: 1.17, 9.22); caffeine remained protective [3].
• This review provides a brief overview of known information on the human toxicity of theobromine and paraxanthine [4].
• Paraxanthine was the principal metabolite in all the three groups with Cmax significantly higher in healthy children (1.3 +/- 0.3 microg/ml) than in children with malaria (0.8 +/- 0.4 microg/ml) (P < 0.05) and kwashiorkor (0.3 +/- 0.1 microg/ml) (P < 0.0001) [5].

Psychiatry related information on p-Xanthine

• Subjects were phenotyped for CYP1A2 activity at 6, 4, and 1 day before smoking cessation and at 0, 1, 2, 3, 6, 8, 10, and 13 days thereafter by use of the paraxanthine-to-caffeine ratio in plasma 6 hours after a 148-mg caffeine test dose [6].
• A high dose of a D-2 antagonist (sulpiride 100 mg/kg) caused a marked inhibition of the locomotor activity induced by bromocriptine, 5 mg/kg, plus 25 mg/kg of caffeine, paraxanthine or theophylline [7].

High impact information on p-Xanthine

• METHODS: In a nested case-control study, we measured serum paraxanthine in 591 women who had spontaneous abortions at less than 140 days' gestation and in 2558 matched women from the same clinic who gave birth to live infants at 28 weeks' gestation or later and who had serum drawn on the same day of gestation as the women who had abortions [1].
• For instance studies indicate that caffeine and its major metabolite paraxanthine suppress neutrophil and monocyte chemotaxis, and also suppress production of the pro-inflammatory cytokine tumour necrosis factor (TNF)-alpha from human blood [8].
• Both caffeine and paraxanthine significantly increased diastolic blood pressure, plasma epinephrine levels, and free fatty acids [9].
• The design permitted confirmation of most of the partial results in various experimental settings and contributed new data on the metabolic disposition of TMX, with specific reference to main dimethylxanthine metabolite found in plasma, paraxanthine (1,7-dimethylxanthine) [10].
• While recommending a 'best buy' from amongst the caffeine urinary metabolite ratios, we favour plasma/saliva indices (caffeine half-life or paraxanthine/caffeine ratio in a spot sample) [11].

Chemical compound and disease context of p-Xanthine

• Maternal serum paraxanthine, a caffeine metabolite, and the risk of spontaneous abortion [1].
• Methylxanthines: toxicity to humans. 3. Theobromine, paraxanthine and the combined effects of methylxanthines [4].

Biological context of p-Xanthine

• Silylation of 1-substituted xanthines followed by alkylation at the 7-position provides a facile route to paraxanthine analogs [12].
• Synthesis of paraxanthine analogs (1,7-disubstituted xanthines) and other xanthines unsubstituted at the 3-position: structure-activity relationships at adenosine receptors [12].
• Additionally, in vivo pharmacokinetics of paraxanthine was determined in CYP1A2-null and wild-type mice [13].
• The molar ratio of two compounds (1,7-dimethylxanthine/1,3,7-trimethylxanthine) was used to phenotype CYP1A2, while the molar ratio of two other compounds (5-acetylamino-6-formylamino-3-methyluracil/1-methylxanthine) served to phenotype NAT2 [14].
• The elimination of paraxanthine after its formation did not follow linear kinetics [15].

Anatomical context of p-Xanthine

• Further evaluation of these compounds in H(2)O(2)-treated A549 lung epithelial and RF24 vascular endothelial cells revealed that the decrease in NAD(+)-levels as well as the formation of the poly(ADP-ribose)polymer was significantly prevented by the major caffeine metabolite 1,7-dimethylxanthine [16].
• It is concluded that physiological and low pharmacological concentrations of paraxanthine result in transient, subcontracture increases in [Ca(2+)](i) in resting skeletal muscle, the magnitude of which is related to paraxanthine concentration [17].
• Paraxanthine displaces the binding of [3H]SCH 23390 from rat striatal membranes [18].
• There was no increase from baseline [Ca(2+)](i) when fibers were superfused with paraxanthine and procaine, suggesting that the sarcoplasmic reticulum is the primary Ca(2+) source in the paraxanthine-induced response [17].
• The four methylated xanthine derivatives, caffeine, theophylline, theobromine and paraxanthine, were tested for their ability to override the mitotic block induced by ionizing radiation in the human bladder carcinoma cell line RT112 [19].

Associations of p-Xanthine with other chemical compounds

• Blood samples were analyzed for theobromine, paraxanthine, and theophylline, by high performance liquid chromatography [20].
• A fast HPLC column, 10 x 4.6 mm, packed with 3-microns spherical ODS packing is used with acetonitrile-methanol-buffer pH 4.7 (4:7:89) to achieve separation of theophylline from paraxanthine and matrix components [21].
• RESULTS: Out of the total sample, 46% were homozygous for the variant A, 44% were heterozygous, and 10% were homozygous for the variant C. The ratio of 1,7-dimethylxanthine (17X) plus 1,7-dimethyluric acid divided by caffeine in 0-5 h urine samples from 185 non-smokers did not differ significantly between the three CYP1A2 genotypes [22].
• We present evidence showing that paraxanthine (1,7-dimethylxanthine), the main metabolite of caffeine in man, displaces the binding of [3H]SCH 23390, a radioligand which selectively labels dopamine D-1 receptors when used at low concentrations, from striatal membranes of the rat [18].
• The CYP1A2 indices, oral caffeine clearance (6.2 +/- 3.3 l/h before and 5.7 +/- 4.2 l/h after, p > 0.05) and the 6-h paraxanthine to caffeine serum concentration ratio (0.49 +/- 0.3 before and 0.44 +/- 0.3 after, p > 0.05), were unchanged following clarithromycin dosing [23].

Gene context of p-Xanthine

• The plasma paraxanthine/caffeine ratio was used to measure CYP1A2 activity [24].
• Conversion of the caffeine metabolite 1,7-dimethylxanthine (17X) to 1,7-dimethyl uric acid (17U) is catalyzed primarily by CYP2A6, and this activity can be assayed by comparison of urinary molar ratios of metabolites [25].
• A statistically significant association (log-likelihood ratio = 25.0) between a locus on chromosome 9, which colocalized with the murine Cyp1a2 locus, and the plasma paraxanthine/caffeine ratio was identified [26].
• Both enzymes formed paraxanthine and minor amounts of theobromine; however, trimethyluric acid was exclusively formed by CYP1A1 [27].
• In vitro incubations with P450 1A2 and 5 mM caffeine led primarily to paraxanthine formation (N-3 demethylation), as expected [28].

Analytical, diagnostic and therapeutic context of p-Xanthine

• In this study, we retrospectively analysed four clinical trials comprising 78 subjects to validate the use of the paraxanthine/caffeine ratios in plasma and saliva for CYP1A2 activity [29].
• The +4% bias observed at low concentrations and the high variability (CV 8.3%) of measurements made by HPLC were thus attributed to interference by paraxanthine present in the sample matrix [30].
• The effect of paraxanthine on J(in)K could not be reversed by subsequent perfusion with paraxanthine-free perfusate [31].
• Use of an enzyme immunoassay procedure resulted in a lesser degree of overestimation (142-383%), which was due, in part, to cross-reactivity with extremely high concentrations of caffeine and paraxanthine [32].
• This biosensor is highly specific for caffeine and response to interfering compounds such as theophylline, theobromine, paraxanthine, other methyl xanthines and sugars was found to be negligible [33].

References