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)

The mutagenic potential of 1,3-butadiene and its epoxide metabolites have been measured in a human lymphoblastoid cell line (TK6) and in splenic T cells from exposed B6C3F1 mice. TK6 cells were exposed for 24 h to 0-400 microM 1,2-epoxybutene, 0-800 microM 3,4-epoxy-1,2-butanediol or 0-6 microM diepoxybutane and plated to measure the frequencies of mutations at the hprt and tk loci. All three metabolites were mutagenic at both loci, but diepoxybutane was active at concentrations 100 times lower than epoxybutene or epoxybutanediol. Mice exposed to 625 ppm butadiene for two weeks had an average hprt mutation frequency of 6.2 x 10(-6) in splenic T cells, whereas that in controls was 1.2 x 10(-6). In mice given three daily intraperitoneal doses of epoxybutene at 60, 80 and 100 mg/kg or diepoxybutane at 7, 14 and 21 mg/kg, the average hprt frequencies were 5.4, 4.1 and 8.6 x 10(-6) in those given epoxybutene and 4.6, 9.4 and 13 x 10(-6) in those treated with diepoxybutane. DNA sequencing revealed that 50% of the mutations induced in vivo by butadiene, epoxybutene and diepoxybutane were transition and transversion mutations at AT and GC base-pairs and 50% were frameshift mutations. The mutational spectra obtained are very similar to that produced by ethylene oxide, suggesting that these epoxides act through a similar mechanism.
 ...
PMID:Mutagenicity of 1,3-butadiene and its epoxide metabolites in human TK6 cells and in splenic T cells isolated from exposed B6C3F1 mice. 807 Aug 66

The mutagenic potential of the epoxide metabolites of butadiene (BD) was measured at the tk and hprt loci in TK6 human lymphoblastoid cells. TK6 cells were exposed for 24 h to 0-400 microM 1,2-epoxybutene (EB), 0-800 microM 3,4-epoxy-1,2-butanediol (EBD), or 0-6 microM 1,2,3,4-diepoxybutane (DEB). Treated cells were allowed to grow for several days and then seeded in medium containing either 6-thioguanine or trifluorothymidine to select for hprt- or tk-/- mutants, respectively. All three metabolites were mutagenic at both loci, with DEB exhibiting activity at concentrations approximately 100-fold lower than EB or EBD. At the hprt locus, an induced mutation frequency of 5 x 10(-6) (approximately twice background hprt- frequency) was produced by treatment with 3.5 microM DEB, 150 microM EB and 450 microM EBD. At the tk locus, a similar increase in mutation frequency (total tk-/- frequency) was produced by treatment with 1.0 microM DEB, 100 microM EB and 350 microM EBD. Each epoxide tested was capable of inducing slow growth tk-/- mutants. This mutant phenotype, as shown previously by others, results from large alterations in the tk region which completely remove the active tk allele. In addition, Southern blot analysis revealed that approximately half of DEB-induced hprt- mutants displayed loss of wild-type hprt restriction fragments. No statistically significant increase in the fraction of hprt deletions among EB mutants was observed. The ability of DEB to induce deletions may be related to its ability to form DNA-DNA and DNA-protein cross-links.
 ...
PMID:Mutagenicity of butadiene and its epoxide metabolites: I. Mutagenic potential of 1,2-epoxybutene, 1,2,3,4-diepoxybutane and 3,4-epoxy-1,2-butanediol in cultured human lymphoblasts. 814 85

1,3-Butadiene (BD) is a confirmed rodent carcinogen and a suspect human carcinogen that forms mutagenic epoxide metabolites during biotransformation. Species differences in the roles of individual DNA reactive intermediates in BD mutagenicity and carcinogenicity are not completely understood. Evidence suggests that 1,2:3,4-diepoxybutane (DEB) is responsible for the mutagenic effect induced by exposures to low concentrations of BD in mice and that metabolites of 3-butene-1,2-diol (BD-diol) are involved in the mutagenicity at high exposures in both mice and rats. Two reactive metabolites, 3,4-epoxy-1,2-butanediol (EB-diol) and hydroxymethylvinyl ketone (HMVK), are formed during the biotransformation of BD-diol and could potentially be involved in BD-diol associated mutagenicity. To examine the role of EB-diol in BD-diol mutagenicity we have evaluated the dosimetry of N7-(2,3,4-trihydroxybutyl)guanine (THB-Gua) and N-(2,3,4-trihydroxybutyl)valine (THB-Val) in female B6C3F1 mice and female F344 rats exposed by inhalation to 0, 6, 18 and 36 p.p.m. BD-diol for 4 weeks (6 h/day x 5 days/week). Results showed higher levels of both THB-Gua and THB-Val in mice than in rats. An evaluation of THB-Gua adducts showed virtually no differences between liver and lung for either species, suggesting that EB-diol is stable and is freely circulated. The data also indicated that THB adduct formation began to plateau around 18 p.p.m. in both species. Most importantly, the shape of the dose-response curve for THB adduct formation mimicked the one observed for hypoxanthine-guanine phosphoribosyltransferase (Hprt) mutation frequency. This showed that THB adducts, which are not thought to be responsible for causing the mutations, are good quantitative indicators of mutagenicity in rodents exposed to BD-diol. Although the potential contribution of HMVK still needs to be evaluated, the data suggest that EB-diol is responsible, at least in part, for BD-diol associated mutagenicity in rodents.
 ...
PMID:Quantification of DNA and hemoglobin adducts of 3,4-epoxy-1,2-butanediol in rodents exposed to 3-butene-1,2-diol. 1588 94