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)

The ability of the potential chemopreventive agent S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) to protect against radiation-induced mutagenesis at the hprt locus and cell killing was studied using CHO-AA8 cells incubated for 30 min at 37 degrees C in growth medium containing its active thiol 2-[(aminopropyl)amino]ethane-thiol (WR-1065). In parallel experiments, the thiol and disulfide forms of the drug present in cells and incubation medium were determined in order to identify which, if either, of the components were associated with the observed protective effects. Treatment with 4 mM WR-1065 produced significant intracellular levels of the thiol (WRSH) and disulfide (WRSS) forms of the drug, but also caused dramatic elevation of cellular glutathione (GSH) and cysteine levels, accompanied by marked protection against 60Co gamma-photon- and neutron-induced cell killing and mutagenesis. When drug-treated cells were transferred to drug-free medium and incubated for 4 h at 37 degrees C, levels of WRSH and WRSS and protection against cell killing decreased markedly, whereas levels of GSH and cysteine and protection against mutagenesis showed little change. GSH and cysteine levels were not associated with protection against radiation-induced mutagenesis, as established by experiments performed with buthionine sulfoximine to block GSH synthesis. These data do not support the hypothesis that modulation of GSH or cysteine levels by WR-1065 is a major mechanism accounting for protection. Protection against mutagenesis was seen for cells incubated in medium with concentrations of added WR-1065 as low as 10 microM, where cellular levels of WRSH and WRSS became difficult to measure (< or = 5 microM) and no protection against cell killing was found. An unexpected observation was that cells incubated in 40 microM WR-1065 incorporated the drug much more rapidly than expected for uptake by passive diffusion and concentrated the drug to a marked degree; this indicates that a cell-mediated transport system is involved in the uptake of WR-1065 at low drug concentrations.
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PMID:Thiol and disulfide metabolites of the radiation protector and potential chemopreventive agent WR-2721 are linked to both its anti-cytotoxic and anti-mutagenic mechanisms of action. 772 53

The cancer chemotherapy drug bleomycin (BLM) is a potent inducer of genetic damage in a wide variety of assays. The radioprotectors cysteamine (CSM) and WR-1065 have been shown in previous studies to potentiate the induction of micronuclei and chromosome aberrations by BLM in Go human lymphocytes. By contrast, WR-1065 is reported to reduce the induction of hprt mutations by BLM in Chinese hamster cells. To elucidate the basis for these interactions, we examined the effects of CSM and WR-1065 on the induction of mitotic gene conversion by BLM in the yeast Saccharomyces cerevisiae. Treatment with BLM causes a dose-dependent increase in the frequency of mitotic gene conversion and gene mutations. Unlike its potentiation of BLM in Go lymphocytes, WR-1065 protected against the recombinagenicity of BLM in yeast. CSM was also strongly-antirecombinagenic under, some conditions, but the nature of the interaction depended strongly on the treatment conditions. Under hypoxic conditions, cysteamine protected against BLM, but under oxygen-rich conditions CSM potentiated the genetic activity of BLM. The protective effect of aminothiols against BLM may be ascribed to the depletion of oxygen required for the activation of BLM and the processing of BLM-induced damage. Aminothiols may potentiate the effect of BLM by acting as an electron source for the activation of BLM and/or by causing conformational alterations that make DNA more accessible to BLM. The results indicate that aminothiols have a strong modulating influence on the genotoxicity of BLM in yeast as they do in other genetic assays. Moreover, the modulation differs markedly depending on physiological conditions. Thus, yeast assays help to explain why aminothiols have been observed to potentiate BLM in some genetic systems and to protect against it in others.
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PMID:Modulation of bleomycin-induced mitotic recombination in yeast by the aminothiols cysteamine and WR-1065. 855 41

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.
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PMID:The inhibition of radiation-induced mutagenesis by the combined effects of selenium and the aminothiol WR-1065. 884 79

Aminothiols such as WR-2721 and its active free thiol WR-1065 have previously been shown to reduce mutations resulting from ionizing radiation in exponentially growing cells. In this study, non-dividing human G0 T-lymphocytes were exposed to the aminothiol radioprotective agent, WR-1065, 30 min before or 3 h after external beam gamma-irradiation and subsequently assessed for survival and mutation induction at the hprt locus. Cytotoxicity due to gamma-irradiation was reduced only when the WR-1065 was present during irradiation. The frequency of hprt mutations, however, was reduced regardless of time of administration, although the reduction was statistically significant only when WR-1065 was added 30 min before irradiation (P < 0.01). This is the first study to demonstrate the protective effects of WR-1065 against radiation-induced mutation in a reporter gene using a human non-cycling cell. Hprt mutations arising in vivo in these cells may be useful for monitoring the radioprotective effect of aminothiols in human populations.
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PMID:Hprt mutations in human T-lymphocytes reflect radioprotective effects of the aminothiol, WR-1065. 900 2

Representatives of two classes of thiazolidine prodrug forms of the well-known radioprotective agents L-cysteine, cysteamine, and 2-[(aminopropyl)amino]ethanethiol (WR-1065) were synthesized by condensing the parent thiolamine with an appropriate carbonyl donor. Inherent toxicity of the prodrugs was assessed in V79 cells using a clonogenic survival assay. Protection against radiation-induced cell death was measured similarly after exposure to 0--8 Gy gamma ((137)Cs) radiation. Antimutagenic activity was determined at the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus. All thiazolidine prodrugs exhibited less toxicity than their parent thiolamines, sometimes dramatically so. Protection against radiation-induced cell death was observed for the 2-alkylthiazolidine, 2(R,S)-D-ribo-(1',2',3',4'-tetrahydroxybutyl)thiazolidine (RibCyst), which produced a protection factor at 8 Gy of 1.8; the cysteine analogue, 2(R,S)-D-ribo-(1',2',3',4'-tetrahydroxybutyl)thiazolidine-4(R)-carboxylic acid (RibCys), was less active. RibCyst also exhibited excellent antimutational activity, rivaling that of WR-1065. The 2-oxothiazolidine analogues showed little activity in either determination under the conditions tested, perhaps due to their enhanced chemical and biochemical stability.
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PMID:Thiazolidine prodrugs as protective agents against gamma-radiation-induced toxicity and mutagenesis in V79 cells. 1147 18