Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
 2,385 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Monkeys with surgical unilateral ventromedial tegmental lesions of the brain stem served as models for investigating abnormalities in Parkinson's disease and Lesch-Nyhan syndrome. 2. The animals exhibited some neurological deficits which are similar to those observed in Parkinson's disease or Lesch-Nyhan syndrome. 3. In monkeys with unilateral ventrolateral tegmental lesions, the levels of dopamine and the activities of catecholamine-synthesizing enzymes were reduced on the lesion side of the striatum, and hypokinesia and tremor developed on the contralateral extremities. 4. Dopa or dopamine agonists relieve tremor and evoke abnormal involuntary movements which are similar to the responses observed in patients with Parkinson's disease. 5. The antitremor effect of Dopa is potentiated by catechol-O-methyltransferase inhibition, suggesting a therapeutic potential for these types of agents. 6. Evidence was obtained that stimulation of D2 dopamine receptors by selective dopamine agonists exerts antitremor activity and evokes abnormal involuntary movements. 7. Combined administration of D1 and D2 dopamine agonists seems to enhance the antitremor activity. 8. Partial dopamine agonists exert antitremor activity and produce less severe abnormal involuntary movements than full dopamine agonists. 9. In a group of monkeys with unilateral ventromedial tegmental lesions of the brain stem the administration of mixed D1/D2 dopamine agonists results in the occurrence of self-biting behavior of the forelimb digits and spasticity of the hindlimbs and these symptoms are similar to those observed in patients with Lesch-Nyhan syndrome. 10. The self-biting behavior seems to be associated with the stimulation of central D1 dopamine receptors and therefore the possible involvement of dopamine neuronal abnormalities in Lesch-Nyhan syndrome deserves further investigation.
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PMID:Monkeys with unilateral ventromedial tegmental lesions of the brain stem: models for Parkinson's disease and Lesch-Nyhan syndrome. 250 25

Working memory has been described as a neurocognitive probe of prefrontal brain functioning. Genetic variability related with catechol-O-methyltransferase (COMT) gene (Val158Met polymorphism) has received increasing attention as a possible modulator of working memory tasks in both schizophrenic patients and healthy subjects, although inconsistencies across studies have been found. This may be related to the existence of different working memory components, processes and modalities, which may have different sensitivities to subtle changes in dopamine levels and, therefore, the effect of the underlying COMT Val158Met genetic variability. To test this out a large sample of 521 healthy individuals from the general population were tested on the WCST and three working memory tasks that cover the assessment of verbal and spatial working modalities as well as different components and processes (Letter and Number Sequencing, CPT-IP, Backwards Visual Span). All individuals were genotyped for the rs4680 (Val158Met) polymorphism at the COMT gene. Met carriers showed near-significant better performance in the LNS compared with Val/Val individuals (F = 3.9, df = 1, P = 0.046). Moreover, the analysis for linear trend found that Met allele carriers showed significantly better performance than Val/Val individuals (B = 0.58 P = 0.031), although evidence for a linear trend was not found. None of the WCST indices differed among genotypes. Consistent with the hypothesis that Val158Met polymorphism (COMT gene) might account for individual differences on dopamine-dependent prefrontally related neurocognitive functions, the Letter-Number Sequencing task, which requires not only maintenance but also active manipulation of information seemed to be more sensitive to the disadvantageous Val/Val genotype in a large non-clinical sample.
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PMID:Putative role of the COMT gene polymorphism (Val158Met) on verbal working memory functioning in a healthy population. 1821 17

A unique sensitivity to specific biochemical processes is responsible for selective vulnerability of midbrain dopamine neurons in several diseases. Prior studies have shown these neurons are susceptible to energy failure and mitochondrial dysfunction, oxidative stress, and impaired disposal of misfolded proteins. These neurons also are especially vulnerable to the loss of purine recycling. In the brains of humans or mice with inherited defects of the purine recycling enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), the most prominent defect is loss of basal ganglia dopamine. To investigate the nature of the relationship between HPRT deficiency and dopamine, the mouse MN9D dopaminergic neuronal cell line was used to prepare 10 sublines lacking HPRT. The mutant sublines grew more slowly than the parent line, but without morphological signs of impaired viability. As a group, the mutant sublines had significantly lower dopamine than the parent line. The loss of dopamine in the mutants did not reflect impaired energy status, as judged by ATP levels or vulnerability to inhibitors of energy production. Indeed, the mutant lines as a group appeared energetically more robust than the parent line. The loss of dopamine also was not accompanied by enhanced susceptibility to oxidative stress or proteasome inhibitors. Instead, the loss of dopamine reflected only one aspect of a broad change in the molecular phenotype of the cells affecting mRNAs encoding tyrosine hydroxylase, the dopamine transporter, the vesicular monoamine transporter, monoamine oxidase B, catechol-O-methyltransferase, and GTP-cyclohydrolase. These changes were selective for the dopamine phenotype, since multiple control mRNAs were normal. These studies suggest purine recycling is an intrinsic metabolic process of particular importance to the molecular phenotype of dopaminergic neurons independent of previously established mechanisms involving energy failure, oxidative stress, or proteasome dysfunction.
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PMID:Consequences of impaired purine recycling in dopaminergic neurons. 1831 25

Metabolic activation of 17beta-estradiol (E2) to catechols and quinones together with lack of deactivation constitute risk factors in human breast carcinogenesis. E2-catchols are generated by cytochrome P450-dependent monooxygenases (CYPs). Deactivation of E2, E2-catechols, and E2-quinones is mediated by UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), catechol-O-methyltransferase (COMT), glutathione-S-transferase (GST), and NADPH-quinone-oxidoreductase (QR) isozymes, respectively. The aim of the present study was to quantify mRNA levels of E2-metabolizing isozymes expressed in MCF-7 cells cultured in the presence/absence of steroids by reverse transcription/competitive PCR in relation to the housekeeping gene hypoxanthine-guanine phosphoribosyltransferase and compare them with expression levels in normal human mammary gland (MG) and liver tissue. CYP1A1, 1B1, SULT1A1, 1A2, membrane-bound and soluble COMT, GSTT1, QR1, and UGT2B7 were detected in both tissues and MCF-7 cells; however, most enzymes were expressed at least tenfold higher in liver. Yet, CYP1B1 was expressed as high in breast as in liver and UGTs were not detected in MCF-7 cells cultured with steroids. MCF-7 cells cultured steroid-free additionally expressed CYP1A2 as well as UGT1A4, 1A8, and 1A9. Normal human liver but not MG expressed CYP1A2, 3A4, UGT1A1, 1A3, 1A4, 1A9, and SULT2A1. UGT1A8 was only detected in MCF7 cells but was not found in human liver. Thus, our study provides a comprehensive overview of expression levels of E2-metabolizing enzymes in a popular in vitro model and in human tissues, which will contribute to the interpretation of in vitro studies concerning the activation/deactivation of E2.
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PMID:Gene expression of 17beta-estradiol-metabolizing isozymes: comparison of normal human mammary gland to normal human liver and to cultured human breast adenocarcinoma cells. 1849 89