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)

GSH, the most abundant erythrocyte thiol, is synthesized from its constituent amino acids by two ATP-dependent enzymes present in the mature red cell. Its unusual gamma-glutamyl linkage precludes degradation by any known red cell peptidase. The erythrocyte lacks a complete "gamma-glutamyl cycle" as described by Meister. GSH has important enzymatic and non-enzymatic roles in oxidoreduction reactions. As the specific co-factor of glutathione peroxidase, it participates in the reduction of harmful organoperoxides. Oxidized glutathione is reconverted to GSH via NADPH-dependent, glutathione reductase. NADPH in the red cell is generated solely by the two dehydrogenases of the pentosephosphate shunt. Increased GSH concentrations are normally present in neonatal erythrocytes. For reasons not clear, they are an epiphenomenon in inherited pyrimidine 5'-nucleotidase deficiency. Many syndromes of heterogeneous etiology having in common dyserythropoietic anemia and ineffective erythropoiesis despite a cellular bone marrow also exhibit abnormally high concentrations of red cell GSH as one component of a constellation of metabolic abnormalities. In a single patient with the Lesch-Nyhan syndrome studied by us, erythrocyte GSH was increased. A kindred with dominantly transmitted (or possibly x-chromosome linked) hereditary hemolytic anemia in which the only thus far detected abnormality is increased red cell GSH has also been documented. The fundamental molecular lesion in this syndrome is unknown.
 ...
PMID:Syndromes with increased red cell glutathione (GSH). 744 Feb 25

In order to evaluate the anti-mutagenic effects of the potential chemoprotective compounds selenium and (S)-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-1065), CHO AA8 cells were exposed to both compounds either individually or in combination prior to irradiation. Mutation frequency following exposure to 8 Gy was evaluated by quantitation of the mutations detected at the hprt locus of these cells. Protection against radiation-induced mutation was observed for both 30 nM sodium selenite or 4 mM WR-1065. In addition, the protection against mutation induction provided by the combination of these agents appeared additive. In contrast, sodium selenite did not provide protection against radiation toxicity when provided either alone or in conjunction with WR-1065. In order to evaluate the possible mechanisms of the anti-mutagenic effects observed in these cells, glutathione peroxidase (GPx) activity was evaluated following exposure to the chemopreventative compounds. The addition of sodium selenite to the culture media resulted in a 5-fold increase in GPx activity, which was unaltered by the presence of the WR-1065. Northern analysis of RNA derived from these cells indicated that selenium supplementation resulted in a marginal increase in the mRNA for the cytosolic GPx (GSHPx-1) which was insufficient to account for the stimulation of GPx activity observed in cellular extracts. These results suggest that selenium and WR-1065 offer protection via independent mechanisms and that GPx stimulation remains a possible mechanism of the anti-mutagenic effect of selenium.
 ...
PMID:The inhibition of radiation-induced mutagenesis by the combined effects of selenium and the aminothiol WR-1065. 884 79

The molecular nature of mutations induced by Cd was investigated in this study to elucidate the role of Cd in the initiation of carcinogenesis. Exposing Chinese hamster ovary (CHO)-K1 cells to cadmium acetate markedly decreased the colony-forming ability of cells and induced mutation frequency in the hypoxanthine (guanine) phosphoribosyltransferase (hprt) gene. The mutation frequency induced by Cd at LD30-LD20 doses was approximately 20 times that of untreated cells. D-Mannitol, a scavenger of reactive oxygen species (ROS), significantly protects cells against Cd cytotoxicity and mutagenicity. Furthermore, non-cytotoxic doses of 3-amino-1,2,4-triazole, a catalase inhibitor, potentiates Cd cytotoxicity and mutagenicity. The cellular Cd uptake ability was not altered by the combined treatment with either D-mannitol or 3-amino-1,2,4-triazole. The GSH level and the activities of GSH peroxidase, GSSG reductase, and catalase in cells treated with Cd (4 microM, 4 h) decreased to 78%, 47%, 40%, and 22% of the untreated cells, respectively. Those enzymatic activities recovered to normal levels 8 h after removing Cd. Polymerase chain reaction and DNA sequencing analysis of 54 independent Cd mutants revealed Cd-induced base substitutions, splice mutations, and large genomic deletions. All six types of base substitutions were observed; however, base transversions (22/27; 81%) occurred more frequently than transitions (5/27; 19%). The frequencies of mutations occurring at T.A or G.C base pairs were roughly equal. Results in this study strongly suggest that Cd mutagenicity in CHO-K1 cells is ROS-dependent. Moreover, the unique mutational spectrum induced by Cd implies that specific DNA adducts generated through the interaction of Cd-DNA and ROS may play a role in the mutational specificity.
 ...
PMID:Reactive oxygen species may participate in the mutagenicity and mutational spectrum of cadmium in Chinese hamster ovary-K1 cells. 895 Dec 41

The accumulation of damage to cellular biomolecules, including DNA, over time may play a significant role in the aetiology of the ageing process. We have previously quantified DNA damage and mutation within cultured lymphocytes from healthy human male subjects in three different age groups (35-39, 50-54 and 65-69 years). The results of that study showed an age-related increase in DNA damage and mutations in lymphocytes. In addition, an age-related decrease in the capacity of the lymphocytes to repair H2O2-induced DNA damage was found. In this article, we report the findings of an extension to the earlier study. Thirty-one generally healthy male and female subjects between the ages of 75 and 80 years were recruited. Using a number of bioassays, we were able to determine; basal levels of DNA damage (for 18 subjects) and mutant frequency at the hypoxanthine phosphoribosyltransferase (hprt) gene locus (for 16 subjects) within cultured lymphocytes. In addition, in vivo antioxidant status (for all study subjects) and the capacity of lymphocytes to repair H2O2-induced DNA damage (for 18 subjects) were also assessed. The results obtained showed: that the mean basal level of DNA damage in lymphocytes from subjects in the 75- to 80-year age group (12.6 +/- 4.7%) was similar to that of the 35- to 39-year age group (13.3 +/- 3.3%), p = 0.42 (Mann-Whitney); there was no significant difference between log mean mutant frequency at the hprt gene locus in lymphocytes from the 75- to 80-year age group (0.31 +/- 0.33) compared to that observed in the 35- to 39-year age group (0.24 +/- 0.21; Student's t-test, t = 0.68, p > 0.05). Levels of the antioxidants glutathione peroxidase (GPx EC 1.11.1.9), catalase (CAT; EC 1.11.1.6) and caeruloplasmin (CPL; EC 1.16.3.1) were significantly elevated in the 75- to 80-year age group, compared to the 35- to 39-, 50- to 54- and 65- to 69-year age groups. Levels of bilirubin (BR) were reduced in the 75- to 80-year age group, the decrease being contributed by the female subjects. No differences in levels of superoxide dismutase (SOD; EC 1.15.1.1) or uric acid (UA) were found between the 4 age groups. Following treatment of lymphocytes with H2O2, we did not find any difference in the susceptibility of lymphocytes to DNA damage in the 75- to 80-year age group, compared to the other age groups. The DNA repair capacity in lymphocytes from individuals in the 75- to 80-year age group was similar to that of the 35- to 39-year age group, for all time points assessed. These results highlight the importance of DNA repair processes and antioxidant defence systems for maintaining genomic stability in vivo.
 ...
PMID:In vivo antioxidant status, DNA damage, mutation and DNA repair capacity in cultured lymphocytes from healthy 75- to 80-year-old humans. 921 88

We have investigated the ability of the naturally occurring plant essence vanillin (3-methoxy-4-hydroxybenzaldehyde) to inhibit mutation at the CD59 locus on human chromosome 11 by hydrogen peroxide, N-methyl-N-nitrosoguanidine, mitomycin C and (137)Cs gamma-radiation in human-hamster hybrid A(L) cells. Previous studies using vanillin have suggested that it can inhibit chromosome aberrations induced by hydrogen peroxide and mitomycin C, as well as inhibiting X-ray- and UV-induced mutations at the hprt locus. Other studies with vanillin have shown that it can increase both the toxicity and mutagenicity of ethyl methane sulfonate and increase the induction of sister chromatid exchange by mitomycin C and a variety of other mutagens. The increased sensitivity of the A(L) assay, which is due in part to its ability to detect both small (single locus) and large (multilocus) genetic damage, allows us to measure the effect of vanillin at low doses of mutagen. Vanillin is shown, in these studies, to inhibit mutation induced by hydrogen peroxide, N-methyl-N-nitrosoguanidine and mitomycin C, as well as to enhance the toxicity of these agents. Vanillin had no effect on either toxicity or mutation induced by (137)Cs gamma-radiation. The vanillin-induced potentiation of H(2)O(2) toxicity is shown not to involve inhibition of catalase or glutathione peroxidase. These results show that vanillin is able to inhibit mutation at the CD59 locus and modify toxicity in a mutagen-specific manner. Possible mechanisms to explain the action of vanillin include inhibition of a DNA repair process that leads to the death of potential mutants or enhancement of DNA repair pathways that protect from mutation but create lethal DNA lesions during the repair process.
 ...
PMID:Vanillin (3-methoxy-4-hydroxybenzaldehyde) inhibits mutation induced by hydrogen peroxide, N-methyl-N-nitrosoguanidine and mitomycin C but not (137)Cs gamma-radiation at the CD59 locus in human-hamster hybrid A(L) cells. 1079 12