Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects.

The role of adenosine and its nucleotides in central synaptic transmission.

Publisher Summary This chapter discusses the physiological role of adenosine in the central nervous system (CNS). In particular, the chapter's attention is directed to the actions of adenosine and related purines in the CNS. One of the major advances in the understanding of purine actions in the central nervous system is the characterization of high affinity specific receptors for purines in brain membranes. The physiological actions of purines, the receptors and biochemical actions that underlie these functional responses and behavioral responses to purinergic drugs are considered. There are three different adenosine receptor sites in brain, which can be distinguished primarily by their effects upon adenylate cyclase, their pharmacological properties, and by their ability to bind labeled analogs of adenosine. One of the best-characterized physiological actions of adenosine is the inhibition of the release of neurotransmitters, an action that has been unequivocally established at many peripheral synapses. If one thing remains clear, it is that purines have a multitude of complex actions at every level, including the biochemical, physiological, and behavioral. There remains little question, but that adenosine or other purines constitute important and rather ubiquitous regulators of neuronalactivity in brain. Despite the evidence that purines play a significant role in neural function, it has remained difficult to define the functional role(s) of purines in brain.

The physiological role of adenosine in the central nervous system.

Distribution, biochemistry and function of striatal adenosine A2A receptors

Context Continuing advances in genotyping technologies and the inclusion of DNA collection in observational studies have resulted in an increasing number of genetic association studies. Objective To evaluate the overall progress and contribution of candidate gene association studies to current understanding of the genetic susceptibility to cancer. Data Sources We systematically examined the results of meta-analyses and pooled analyses for genetic polymorphisms and cancer risk published through March 2008. Study Selection We identified 161 meta-analyses and pooled analyses, encompassing 18 cancer sites and 99 genes. Analyses had to meet the following criteria: include at least 500 cases, have cancer risk as outcome, not be focused on HLA antigen genetic markers, and be published in English. Data Extraction Information on cancer site, gene name, variant, point estimate and 95% confidence interval (CI), allelic frequency, number of studies and cases, tests of study heterogeneity, and publication bias were extracted by 1 investigator and reviewed by other investigators. Results These 161 analyses evaluated 344 gene-variant cancer associations and included on average 7.3 studies and 3551 cases (range, 508-19 729 cases) per investigated association. The summary odds ratio (OR) for 98 (28%) statistically significant associations (P value −14 ), NAT2 slow acetylator and bladder cancer (OR, 1.46; 95% CI, 1.26-1.68; P = 2.5 × 10 −7 ), MTHFR C677T and gastric cancer (OR, 1.52; 95% CI, 1.31-1.77; P = 4.9 × 10 −8 ), and GSTM1 null and acute leukemia (OR, 1.20; 95% CI, 1.14-1.25; P = 8.6 × 10 −15 ). When the OR used to determine statistical power was lowered to 1.2, 2 of the 4 noteworthy associations remained so: GSTM1 null with bladder cancer and acute leukemia. Conclusion In this review of candidate gene association studies, nearly one-third of gene-variant cancer associations were statistically significant, with variants in genes encoding for metabolizing enzymes among the most consistent and highly significant associations.

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Genetic Susceptibility to Cancer: The Role of Polymorphisms in Candidate Genes

SummaryCaffeine and theophylline were equally effective in increasing confinement motor activity when administered ip in doses up to 0.10–0.12 mmole/kg. Higher doses of caffeine produced some toxicity as evident from less stimulation of motor activity. Theophylline produced its peak effect at a dose of 0.17 mmole/kg (30 mg/kg). Doses of either xanthine as great as 0.25 mmole/kg produced much less activity than the optimum doses. Equimolecular doses of caffeine and theophylline produced approximately equal brain xanthine levels.

Effects of caffeine and theophylline on activity of rats in relation to brain xanthine concentrations.

The involvement of phase I and II enzymes is well documented in the metabolism of a wide range of drugs and xenobiotics Single-nucleotide polymorphisms (SNPs) of these enzymes are also known to alter their protein expression and function Moreover, genetic susceptibility and environmental exposure have been proposed to be an etiology of cancer We hypothesized that polymorphisms of these enzymes might affect the risk of childhood acute lymphoblastic leukemia (ALL) CYP 1A1, CYP 3A4*1B, CYP 3A5*3, CYP 3A5*6, GSTM1, and GSTT1 polymorphisms were genotyped by using PCR-RFLP in 107 children with ALL and 320 healthy controls Allele and genotype frequencies of each of the SNPs were compared between two groups It was found that the allele frequencies of CYP 1A1*1, *2A, *2B, and *4 were not different between cases and controls CYP 3A4*1B allele frequency was only 08% and 09% in ALL and controls, respectively CYP 3A5*1/*1, *1/*3, and *3/*3 genotype frequencies showed no statistically significant difference between patients and controls CYP 3A5*6 was not detected in our population The GSTM1 null genotype was significantly increased in children with ALL (OR 17; 95% CI, 10, 27) In contrast, the GSTT1 null genotype did not show this effect Our data thus demonstrate that the GSTM1 null genotype might increase the risk of childhood ALL in a Thai population Am J Hematol 79:202–205, 2005 © 2005 Wiley-Liss, Inc

Polymorphisms of drug-metabolizing enzymes and risk of childhood acute lymphoblastic leukemia.

Background. Polymorphisms of DNA repair genes can alter protein structure and may impair DNA repair capacity. Defects in repairing damaged DNA lead to genetic instability and carcinogenesis. This study was performed to evaluate the effect of the polymorphisms of DNA repair genes on risk of childhood acute lymphoblastic leukemia (ALL). Procedures. We genotyped polymorphisms of X-ray repair cross-complimenting group 1 (XRCC1) codon 194 (Arg to Trp), 280 (Arg to His) and 399 (Arg to Gln), and xeroderma pigmentosum group D (XPD) codon 312 (Asp to Asn) and 715 (Lys to Gln) in 108 children with ALL and 317 healthy controls using PCR-RFLP method. The allele, genotype, and haplotype frequencies of these polymorphisms were compared between cases and controls using Chi-square or Fisher’s exact test. PHASE computer software was used to analyze estimated haplotypes of the XRCC1 and XPD polymorphisms. Results. The frequency of XRCC1 194Trp allele in patients was significantly lower than that in controls (odds ratio (OR) 0.67; 95% confidence interval (CI), 0.47–0.97). Individuals with XRCC1 194 Trp/Trp genotype had a significantly reduced risk of ALL (OR 0.22; 95% CI, 0.05–0.96). The frequency of the XRCC1 haplotype B (194Trp-280Arg-399Arg) was significantly lower in children with ALL when compared to controls. The XRCC1 399Gln allele was associated with a significantly increased risk of ALL (OR 1.67; 95% CI, 1.20–2.33). The frequency of the XRCC1 haplotype C (194Arg-280Arg-399Gln) was significantly higher in patients. There was no difference of allele frequencies of the XRCC1 280 (Arg to His), XPD 312 (Asp to Asn), or XPD 715 (Lys to Gln) between cases and controls. Conclusion. The XRCC1 194Trp allele and haplotype B showed a protective effect against development of childhood ALL. In contrast, individuals with the XRCC1 399Gln allele and haplotype C were associated with increased risk for this disease. Pediatr Blood Cancer 2007;48: 16–20. 2006 Wiley-Liss, Inc.

Genetic polymorphisms and haplotypes of DNA repair genes in childhood acute lymphoblastic leukemia

Dear Editor,Methotrexate (MTX) inhibits several enzymes in folatemetabolic pathway, including dihydrofolate reductase,thymidylate synthase (TYMS), and methylenetetrahydrofo-late reductase (MTHFR), causing defects in DNA and RNAsyntheses and methylation process [1]. Genetic polymor-phisms of genes encoding proteins in folate metabolismaffect their structures and functions. MTHFR C677T andA1298C are associated with decreased enzyme activity andhyperhomocysteinemia [1]. There are 28 nucleotide-tandemrepeat variations in 5’untranslated region of the TYMSgene. The most common variations of this polymorphismare two and three repeats (2R and 3R). TYMS gene with3R polymorphism has a higher expression level than theone with 2R [1, 2]. Reduced folate carrier (RFC) is anessential carrier protein for folate and MTX. RFC G80Apolymorphism affects MTX level in patients treated withhigh dose of MTX. MTX level has been found to besignificantly higher in patients with RFC 80 AA genotypethan other genotypes [1, 3].Our institute normally uses two courses of high-doseMTX (1.5 g/m

Genetic polymorphisms of folate metabolic enzymes and toxicities of high dose methotrexate in children with acute lymphoblastic leukemia.

The effects of caffeine on the pharmacokinetics and bioavailability of aspirin were studied in 12 healthy adult male volunteers The subjects received 650 mg of aspirin or 650 mg of aspirin with 120 mg of caffeine citrate orally It was found that caffeine significantly increased the rate of appearance as well as the maximum concentration of salicylate in the plasma by about 25% and 17%, respectively Moreover, area under the plasma concentration-time curve of salicylate was significantly higher in the subjects given the drug combination as compared to those given aspirin alone There was no change in the plasma half-life, volume of distribution and clearance of salicylate

Amnuay Thithapandha

Papers

Effects of caffeine and theophylline on activity of rats in relation to brain xanthine concentrations.

Polymorphisms of drug-metabolizing enzymes and risk of childhood acute lymphoblastic leukemia.

Genetic polymorphisms and haplotypes of DNA repair genes in childhood acute lymphoblastic leukemia

Genetic polymorphisms of folate metabolic enzymes and toxicities of high dose methotrexate in children with acute lymphoblastic leukemia.

Influence of caffeine on aspirin pharmacokinetics.