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

Chlorambucil (CBC) is used as a chemotherapeutic agent and immunosuppressant. Recently, it could be shown that CBC is considerably more effective than radiation or any chemical investigated to date in inducing high yields of germ-line mutations that appear to be multilocus deletions or other structural changes. We therefore reinvestigated the in vitro genotoxic effects of CBC in V79 cells and characterized induced sister-chromatid exchanges (SCEs), chromosome aberrations and gene mutations by means of cytogenetic and molecular methods. CBC effectively induced chromosome aberrations and SCEs in a dose-dependent manner. The chromosome aberrations found after a 14-h treatment were mainly chromatid-type aberrations. 3-Aminobenzamide (3AB) did not influence the incidence of CBC-induced SCEs and chromosome aberrations. Combined treatment with CBC and caffeine (CAF) strongly increased the frequency of aberrations, but had no effect on the yield of SCEs. CAF at lower concentrations enhanced the production of chromatid breaks and exchange figures while higher concentrations (10(-3) M) caused multiple breaks and pulverised mitoses. Mutations at the hprt locus were induced in a narrow range of CBC concentrations (10(-5) M-2 x 10(-5) M) and the mutagenic effect was accompanied by strong cytotoxicity. The CBC-induced gene mutation frequency was not increased after CAF treatment. The molecular analysis of CBC-induced mutations by Southern hybridization and PCR demonstrated that CBC predominantly produced small alterations but not deletions or gross structural alterations in the hprt gene of V79 cells. For the first time, these results reveal striking differences in the mutagenic action of an alkylating agent in cultivated cells compared to germ-line cells at the molecular level.
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PMID:Cytogenetic and molecular characterization of the mutagenicity of chlorambucil in V79 cells. 138 Jun 68

A prospective, longitudinal study was performed to test the hypothesis that environmental factors (e.g., diet or cigarette smoking) modulate genetic damage caused by treatment for breast cancer and render these women more susceptible to developing second malignancies. A total of 107 women (49 with breast cancer, 52 with benign breast masses, and 6 normal women) were enrolled. This report describes initial studies at the time of enrollment and disease presentation. Mutant frequency at the hprt locus and cloning efficiency of peripheral blood lymphocytes did not differ significantly among the 3 groups. Mutant frequency increased with age, with a history of cigarette smoking, and with the number of years that current smokers used cigarettes. There was no correlation in women with benign masses between mutant frequency and the incidence of chromosome aberrations (28 women) or sister chromatid exchanges (23 women). A maternal history of breast cancer did not influence mutant frequency. There was no significant relationship between dietary intake of vitamins A, B12, C and E, folacin, selenium, calcium, caffeine, or multivitamin pills, and mutant frequency. Serum folate levels in the deficient range were associated (P = 0.02) with elevated mutant frequencies, whereas SCE rates inversely correlated with serum vitamin B12 levels. These results confirm the importance of age and, less so, cigarette smoking as factors that influence mutant frequency and suggest that a micronutrient, folic acid, may modify genetic damage at the hprt locus. To the extent that somatic mutation contributes to carcinogenesis, these environmental factors may enhance the risk of developing malignant transformation.
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PMID:Factors influencing mutation at the hprt locus in T-lymphocytes: studies in normal women and women with benign and malignant breast masses. 160 Sep 53

Southern blot analyses were performed on DNA from at least 10 large and 10 small colony thymidine kinase-deficient (tk -/-) mutants induced by each of 10 mutagens [2-amino-N6-hydroxyadenine (AHA), ethyl methanesulfonate (EMS), methyl methanesulfonate, 2-acetylaminofluorene, methotrexate, caffeine, methapyrilene, 4-(9-acridinylamino)-methanesulfo-m-anisidide, hycanthone methanesulfonate and procarbazine]. Two molecular mutant genotypes were recognized upon digestion with NcoI and subsequent probing with a 1.1 kb cDNA insert from plasmid pMtk 4: (i) no detectable alteration, and (ii) the absence of the functional tkb allele as indicated by the absence of the 6.3 kb fragment. In combination with the previously established chromosomal nature of most small colony tk -/- mutants, this permitted the classification of these 10 mutagens according to the relative proportions of each of four classes of genetic damage they induced. AHA and EMS gave mutational spectra consistent with their point mutational effects in other systems. The other eight mutagens induced mostly small colony mutants, most of which had lost the entire original tkb allele. Methotrexate induced high frequencies of large colony mutants at the tk locus, most of which lacked the tkb allele, although it is weakly or non-mutagenic at the hemizygous hprt locus in these same cells. At least three of these mutagens-methotrexate, caffeine, methapyrilene (and possibly procarbazine)--lack structural alerts for DNA reactivity, implying a major class of non-DNA primary targets for mutagenicity in mammalian cells that interact secondarily with the chromosome. These results are discussed in relation to the known differences in sensitivity among various short-term tests for genotoxicity.
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PMID:Molecular aspects of chemical mutagenesis in L5178Y/tk +/- mouse lymphoma cells. 218 74

The CHO-UV-1 mutant, a Chinese hamster ovary cell with defective postreplication recovery of DNA, is 2- to 4-fold more sensitive than its wild-type counterpart (CHO-77256) to the lethal effects of ethylating agents and UV radiation; it is also hypersensitive (10- to 20-fold) to some DNA-methylating and -cross-linking agents. We studied the CHO-UV-1 mutant further to define its phenotype in terms of DNA damage induction and repair, methyltransferase activity, and effects of caffeine on mutational and lethal responses. Both wild-type and CHO-UV-1 cells incurred similar levels and types of damage when exposed to UV radiation, N-methyl-N'-nitro-N-nitrosoguanidine, or N-methyl-N-nitrosourea. The rate and extent of repair of Micrococcus luteus endonuclease-sensitive sites after UV irradiation or treatment with N-methyl-N'-nitro-N-nitrosoguanidine were also equivalent in these two cell types. Twenty % of the initial endonuclease-sensitive sites induced in either cell line remained at 18 h after UV irradiation; approximately 8% of the sites after N-methyl-N'-nitro-N-nitrosoguanidine exposure were present in both parental and CHO-UV-1 cells after a 17-h repair period. Moreover, the ability of CHO-UV-1 to resynthesize and ligate DNA during excision repair was similar to that of its parent. Neither CHO-UV-1 nor CHO-77256 had appreciable levels of O6-methylguanine-DNA methyltransferase activity which ameliorates the cytotoxicity of alkylating agents. Caffeine, a known inhibitor of postreplication repair, decreased the frequency of mutation induction at the hypoxanthine-guanine phosphoribosyltransferase locus by 40-55% in CHO-77256 but not in CHO-UV-1. These results rule out defective excision repair as a factor in the hypersensitivity of the CHO-UV-1 mutant to DNA-damaging agents. Hence, this cell line appears to derive from a mutation affecting nonexcision repair processes and should be useful in clarifying the mechanism(s) of postreplication recovery of DNA in mammalian cells.
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PMID:Genetic and biochemical characterization of the CHO-UV-1 mutant defective in postreplication recovery of DNA. 231 21

The free amino acid content in the cerebral cortex of rats administered caffeine orally, and with automutilation behavior similar to that observed in the Lesch-Nyhan syndrome, have been measured. Amino acids significantly elevated were taurine, histidine and aspartic acid, whereas tyrosine showed a significant reduction. There was no change in the concentration of gamma-aminobutyric acid and glutamic acid. It has been conjectured that changes in amino acids levels in the cortex might be responsible for the pharmacological action of caffeine and for the progressive behavior abnormalities observed in these rats. Interestingly these results are similar to these found recently in experimental uremia.
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PMID:Caffeine-induced changes in the composition of the free amino acid pool of the cerebral cortex. 404 83

Rats ingesting high doses of caffeine reproduce the self-destructive behaviour observed in the Lesch-Nyhan syndrome. This syndrome includes a deficit in hypoxanthine-guanine phosphoribosyltransferase. We have observed, however, that the activity of hypoxanthine-guanine phosphoribosyltransferase increases in direct proportion to the concentration of caffeine found in rat brain. It appears, therefore, that the caffeine model is not a true model for the Lesch-Nyhan syndrome, or alternatively, that the deficit in hypoxanthine-guanine phosphoribosyltransferase is coincidental and not a main key to the multifarious aspects of the syndrome, particularly the self-mutilation. The possibility that levels of dopamine are increased in the caffeine model are discussed as a basis for the destructive behaviour. We have found also that ingestion of large amounts of caffeine increases the activities in rat brain of adenosine deaminase, purine nucleoside phosphorylase, aspartate carbamoyl-transferase, dihydroorotase, and dihydroorotate oxidase.
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PMID:Lesch-Nyhan syndrome, caffeine model: increase of purine and pyrimidine enzymes in rat brain. 614 65

Self-biting (SB) is an unusual behavioral effect of high doses of certain amphetamine-like drugs in rats. This bizarre behavior has received little attention, perhaps because the high doses of drug required and the dramatic disturbance of the animals' behavioral repertoire have raised the possibility that SB is a high dose phenomenon. However, we have found that continuous administration of very low amounts of amphetamine reliably produces SB in rats, and that this behavioral change can be very selective. We compared SB produced by continuous amphetamine to SB produced by daily caffeine; the latter has been proposed as an animal model for self-injurious behavior (SIB) in the Lesch-Nyhan syndrome. Subcutaneous silicone pellets containing amphetamine base were implanted for 4.5 days; caffeine was administered daily for 10 days. The amphetamine pellets produced the highest rate of SB (75% vs 40%) with the least toxic effects (no deaths vs three deaths). Neither drug produced stereotypy. The dopamine antagonist haloperidol was only marginally effective in controlling SB produced by daily caffeine but the dopamine antagonist pimozide (which has a longer duration of action) prevented SB by amphetamine pellet rats. Continuous release amphetamine pellets may provide an alternative to the caffeine model of SIB in humans, particularly for the Lesch-Nyhan syndrome.
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PMID:Self-injurious behavior produced in rats by daily caffeine and continuous amphetamine. 689 Oct 61

Caffeine, theophylline or aminophylline were administered chronically to rats of both sexes, in the weight range 30-245 g. Self-injurious behaviour was noted only rarely in Wistar rats allowed free access to food, but developed over 3 to 4 weeks in half of the animals given a restricted diet of about one third of the intake of control rats. Fischer rats showed self-injurious behaviour more readily, 87% of animals showing signs within 9 days even on an ad lib diet. It is suggested that Fischer rats treated with methylxanthines may provide a model of the Lesch-Nyhan syndrome. Behavioural observations made during the period of methylxanthine treatment suggest that an activation of both the dopamine and 5-hydroxytryptamine neurone systems may be produced. Further work will seek a relationship between these systems and self-injurious behaviour.
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PMID:Chronic methylxanthine treatment in rats: a comparison of Wistar and Fischer 344 strains. 725 18

The ability to bypass DNA lesions encountered during replication is important in order to maintain cell viability and avoid genomic instability. Exposure of mammalian cells to UV-irradiation induces the formation of DNA lesions that stall replication forks. In order to restore replication, different bypass mechanisms are operating, previously named post-replication repair. Translesion DNA synthesis is performed by low-fidelity polymerases, which can replicate across damaged sites. The nature of lesions and of polymerases involved influences the resulting frequency of mutations. Homologous recombination represents an alternative pathway for the rescue of stalled replication forks. Caffeine has long been recognized to influence post-replication repair, although the mechanism is not identified. Here, we found that caffeine delays the progress of replication forks in UV-irradiated Chinese hamster cells. The length of this enhanced delay was similar in wild-type cells and in cell deficient in either homologous recombination or nucleotide excision repair. Furthermore, caffeine attenuated the frequency of UV-induced mutations in the hprt gene, whereas the frequency of recombination, monitored in this same gene, was enhanced. These observations indicate that in cells exposed to UV-light, caffeine inhibits the rescue of stalled replication forks by translesion DNA synthesis, thereby causing a switch to bypass via homologous recombination. The biological consequence of the former pathway is mutations, while the latter results in chromosomal aberrations.
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PMID:Caffeine delays replication fork progression and enhances UV-induced homologous recombination in Chinese hamster cell lines. 1696 77