Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
 2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1,3-Butadiene (BD) is carcinogenic in mice and rats, with mice being more susceptible than rats to its carcinogenic effects. 1,3-Butadiene is mutagenic in the bone marrow and spleen cells of B6C3F1 lacI transgenic mice. The goal of this research was to assess the roles of two BD metabolites, 1,2-epoxy-3-butene (BDO) and 1,2,3,4-diepoxybutane (BDO2), in the mutagenicity and mutational spectrum of the parent compound BD by determining the mutagenicity and mutational spectra of BDO and BDO2 in human and rodent cells in vitro and in vivo. In human TK6 lymphoblastoid cells (TK6 cells), BDO exposure increased the frequency of G.C-->A.T transitions and A.T-->T.A transversions (Fisher exact test; p < 0.05). The most striking difference in the type of base-substitution mutations between BDO-exposed and BDO-unexposed TK6 cells was the 19-fold increase in A.T-->T.A transversions. 1,2,3,4-Diepoxybutane increased the frequency of A.T-->T.A transversions (Fisher exact test; p < 0.05) and the frequency of deletions in exposed TK6 cells compared with unexposed controls. Exposure of Rat2 lacI transgenic fibroblasts (Rat2 cells) to BDO increased the frequency of three types of base-substitution mutations: G.C-->A.T transitions, G.C-->T.A transversions, and A.T-->T.A transversions. Exposure of Rat2 cells to BDO2-induced dose-dependent increases in micronuclei at exposure levels that apparently did not induce mutagenicity at the lacI transgene. The lack of detectable mutagenicity at the lacI transgene in Rat2 cells exposed to BDO2 probably reflects the poor recovery of large deletions by this lambda phage-based mutagenicity assay. Inhalation exposure of B6C3F1 lacI transgenic mice (lacI mice) and F344 lacI transgenic rats (lacI rats) to BDO (29.9 parts per million [ppm]; 6 hours/day; 5 days/week for 2 weeks) did not increase the lacI mutant frequency (MF) in bone marrow or spleen cells of mice and rats, but in the cells of mouse lung (a tumor target organ for BD), significant mutagenicity was observed. An increased lacI MF was also observed in the bone marrow cells of rats exposed to BDO. Inhalation exposure of lacI mice and lacI rats to BDO2 (3.8 ppm; 6 hours/day; 5 days/week for 2 weeks) did not increase the lacI MF in bone marrow or spleen cells of mice or in the spleen cells of rats. An increased lacI MF was observed in the bone marrow cells of rats exposed to BDO2. In the present study, BDO specifically induced G.C-->A.T and A.T-->T.A transversions in vitro at both the endogenous hypoxanthine phosphoribosyltransferase (hprt) gene and the lacI transgene in Rat2 cells. It also induced an increased frequency of G.C-->T.A transversions in Rat2 cells. These types of mutations also occur at an increased frequency in mice exposed to the parent compound, BD. This finding demonstrates the induction of consistent mutational types across biological systems by BDO and indicates that BDO, but not BDO2, probably has a role in mediating the mutations recovered at the lacI transgene in animals exposed to the parent compound, BD. Therefore, it is apparent that in mice exposed to BD at carcinogenic levels, BDO and BDO2 act in concert to mediate the range of genotoxic responses. These data demonstrate that certain DNA adducts (guanine or adenine) may be useful biomarkers for BD genetic effects. However, other DNA lesions that can account for BDO2-induced deletions and chromosomal alterations also need to be considered as biomarkers for BD-induced genotoxicity.
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PMID:1,3-butadiene: cancer, mutations, and adducts. Part II: Roles of two metabolites of 1,3-butadiene in mediating its in vivo genotoxicity. 1092 39

1,3-Butadiene (BD), an important chemical used mainly in the production of synthetic rubber, is a potent carcinogen in mice, a weak carcinogen in rats, and a suspected carcinogen in humans. To provide a better understanding of the mutagenic mechanisms involved in interspecies differences in BD-induced carcinogenesis, studies were conducted in rodents to test two hypotheses: (a) the mutagenic potency of BD at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus of T lymphocytes (T cells) can be used to quantify interspecies differences in BD-induced carcinogenicity in exposed rodents and (b) comparison of the mutagenic potency and specificity of BD and racemic mixtures of two epoxy metabolites, 1,2-epoxy-3-butene (BDO) and 1,2,3,4-diepoxybutane (BDO2), at the hprt locus of T cells can be used to define the relative contribution of each intermediate to observed BD mutagenicity in each species. The first hypothesis was investigated by determining the effects of exposure duration and elapsed time after exposures on hprt mutant frequencies (MFs) in T cells from thymus and spleen of female B6C3F1 mice and F344 rats (4 to 5 weeks old). In this study, rodents were exposed by inhalation to 0 or 1,250 parts per million (ppm) BD for up to 2 weeks, or to 0 or 625 ppm BD for up to 4 weeks (with all exposures 6 hours/day, 5 days/week). The second hypothesis was examined by defining the effects of exposure concentration and elapsed time after exposures on the hprt MFs in splenic T cells from mice and rats exposed by inhalation to BD (0, 20, 62.5, or 625 ppm), BDO (0, 2.5, or 25 ppm), or BDO2 (0, 2, or 4 ppm) for 4 weeks (all exposures 6 hours/day, 5 days/week). The hprt MFs were measured weekly or biweekly using the T cell cloning assay for up to 10 weeks after the last exposure. The mutagenic potency of BD (represented by the difference in the areas under the mutant T cell "manifestation" curves [or the "change in MFs over time"] of exposed versus control animals) was significantly greater in mice (4.4-fold) than in rats following 2 weeks of exposure to 1,250 ppm BD. Mutagenic potency in mice was 8.5-fold greater than that in rats following 4 weeks of exposure to 625 ppm BD. These hprt MF data provide the first evidence that BD is mutagenic in the rat, albeit the mutagenic response was significantly less than that observed in similarly exposed mice. In addition, the MF data from the two exposure-duration studies indicate that both exposure concentration and exposure duration are important in determining the magnitude of the mutagenic response to BD. The relative contribution of BDO versus BDO2 to overall BD mutagenicity was evaluated by exposing mice and rats to carefully chosen concentrations of BD and racemic mixtures of BDO and BDO2 (that is, 62.5, 2.5, and 4.0 ppm, respectively) and comparing the mutagenic potency of each compound when comparable blood levels of metabolites were achieved. The resulting MF data indicate that (+/-)-BDO2 is a major contributor to the mutagenicity of BD in mice at lower BD exposure levels (< or = 62.5 ppm), whereas other metabolites and stereochemical configurations are responsible for mutations in BD-exposed rats and for the incremental mutagenic effects at higher exposure levels in mice. Molecular analysis of hprt cDNA from expanded T cell clones from control and BD-exposed mice demonstrated an increased frequency of large deletions in exposed animals (p = 0.016), presumably associated with in situ formation of (+/-)-BDO2, meso-BDO2, or both. Results of these mutagenicity experiments, along with data from collaborative studies of DNA adducts from the same animals, should provide a better understanding of the interspecies variation in carcinogenic response to BD and improve the extrapolation of rodent data to the estimation of cancer risk in exposed persons.
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PMID:1,3-butadiene: cancer, mutations, and adducts. Part III: In vivo mutation of the endogenous hprt genes of mice and rats by 1,3-butadiene and its metabolites. 1092 40

1,3-Butadiene (BD), which is used to make styrene-butadiene rubber, is a potent carcinogen in mice and a probable carcinogen, associated with leukemia, in humans. We have previously used HPRT mutation as a biomarker to evaluate exposures to BD in a monomer production plant. We now report on a study of 49 workers in a styrene-butadiene rubber plant in which we used the concentration of the BD metabolite 1,2-dihydroxy-4-(N-acetylcysteinyl-S)-butane (M1) in urine as a biomarker of exposure and the frequency of HPRT variant (mutant) lymphocytes (Vf) as a biomarker of effect. Workers were assigned to high- and low-exposure groups based on historical information about work areas and jobs. Personal exposure to BD for one work shift was measured using a passive badge dosimeter. Each participant provided a urine specimen and blood sample at the end of the work shift and completed a questionnaire providing information on lifestyle, health, and work activities. The average BD exposures in the high- and low-exposure groups were significantly different, even after excluding two extreme values, (high 1.48 ppm; low 0.15 ppm, p < 0.002). This study was done in 1994 and 1995 before the establishment, in 1996, of the new permissible exposure limit of 1 ppm. Both the mean M1 and the HPRT Vf were more than three times greater in the high-exposure group than in the low-exposure group (p < 0.0005). The three end points correlated with each other, with sample correlation coefficients between 0.4 and 0.6. The correlations among BD exposure and the biomarkers of internal exposure and genotoxicity suggest that occupational exposure to BD, in the range of 1-3 ppm, may be associated with adverse biological effects.
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PMID:Assessment of 1,3-butadiene exposure in polymer production workers using HPRT mutations in lymphocytes as a biomarker. 1174 32

1,3-Butadiene (BD) is an important industrial chemical and pollutant. Its ability to induce genetic damage and cause hematological malignancies in humans is controversial. We have examined chromosome damage by fluorescence in situ hybridization (FISH) and mutations in the HPRT gene in the blood of Chinese workers exposed to BD. Peripheral blood samples were collected and cultured from 39 workers exposed to BD (median level 2 ppm, 6 h time-weighted average) and 38 matched controls in Yanshan, China. No difference in the level of aneuploidy or structural changes in chromosomes 1, 7, 8, and 12 was detected in metaphase cells from exposed subjects in comparison with matched controls, nor was there an increase in the frequency of HPRT mutations in the BD-exposed workers. Because genetic polymorphisms in glutathione S-transferase (GST) enzymes and microsomal epoxide hydrolase (EPHX1) may affect the genotoxic effects of BD and its metabolites, we also related chromosome alterations and gene mutations to GSTT1, GSTM1 and EPHX1 genotypes. Overall, there was no effect of variants in these genotypes on numerical or structural changes in chromosomes 1, 7, 8 and 12 or on HPRT mutant frequency in relation to BD exposure, but the GST genotypes did influence background levels of both hyperdiploidy and HPRT mutant frequency. In conclusion, our data show no increase in chromosomal aberrations or HPRT mutations among workers exposed to BD, even in potentially susceptible genetic subgroups. The study is, however, quite small and the levels of BD exposure are not extremely high, but our findings in China do support those from a similar study conducted in the Czech Republic. Together, these studies suggest that low levels of occupational BD exposure do not pose a significant risk of genetic damage.
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PMID:Lack of increased genetic damage in 1,3-butadiene-exposed Chinese workers studied in relation to EPHX1 and GST genotypes. 1503 20

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.
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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