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 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

Results of a recent molecular epidemiological study of 1,3-butadiene (BD) exposed Czech workers, conducted to compare female to male responses, have confirmed and extended the findings of a previously reported males only study (HEI Research Report 116, 2003). The initial study found that urine concentrations of the metabolites 1,2-dihydroxy-4-(acetyl) butane (M1) and 1-dihydroxy-2-(N-acetylcysteinyl)-3-butene (M2) and blood concentrations of the hemoglobin adducts N-[2-hydroxy-3-butenyl] valine (HB-Val) and N-[2,3,4-trihydroxy-butyl] valine (THB-Val) constitute excellent biomarkers of exposure, both being highly correlated with BD exposure levels, and that GST genotypes modulate at least one metabolic pathway, but that irreversible genotoxic effects such as chromosome aberrations and HPRT gene mutations are neither associated with BD exposure levels nor with worker genotypes (GST [glutathione-S-transferase]-M1, GSTT1, CYP2E1 (5' promoter), CYP2E1 (intron 6), EH [epoxide hydrolase] 113, EH139, ADH [alcohol dehydrogenase]2 and ADH3). The no observed adverse effect level (NOAEL) for chromosome aberrations and HPRT mutations was 1.794 mg/m(3) (0.812 ppm)--the mean exposure level for the highest exposed worker group in this initial study. The second Czech study, reported here, initiated in 2003, included 26 female control workers, 23 female BD exposed workers, 25 male control workers and 30 male BD exposed workers (some repeats from the first study). Multiple external exposure measurements (10 full 8-h shift measures by personal monitoring per worker) over a 4-month period before biological sample collections showed that BD workplace levels were lower than in the first study. Mean 8-h TWA exposure levels were 0.008 mg/m(3) (0.0035 ppm) and 0.397 mg/m(3) (0.180 ppm) for female controls and exposed, respectively, but with individual single 8-h TWA values up to 9.793 mg/m(3) (4.45 ppm) in the exposed group. Mean male 8-h TWA exposure levels were 0.007 mg/m(3) (0.0032 ppm) and 0.808 mg/m(3) (0.370 ppm) for controls and exposed, respectively; however, the individual single 8-h TWA values up to 12.583 mg/m(3) (5.72 ppm) in the exposed group. While the urine metabolite concentrations for both M1 and M2 were elevated in exposed compared to control females, the differences were not significant, possibly due to the relatively low BD exposure levels. For males, with greater BD exposures, the concentrations of both metabolites were significantly elevated in urine from exposed compared to control workers. As in the first study, urine metabolite excretion patterns in both sexes revealed conjugation to be the minor detoxification pathway (yielding the M2 metabolite) but both M1 and M2 concentration values were lower in males in this second study compared to their concentrations in the first, reflecting the lower external exposures of males in this second study compared to the first. Of note, females showed lower concentrations of both M1 and M2 metabolites in the urine per unit of BD exposure than did males while exhibiting the same M1/(M1+M2) ratio, reflecting the same relative utilization of the hydrolytic (producing M1) and the conjugation (producing M2) detoxification pathways as males. Assays for the N,N-(2,3-dihydroxy-1,4-butadyl) valine (pyr-Val) hemoglobin (Hb) adduct, which is specific for the highly genotoxic 1,2,3,4-diepoxybutane (DEB) metabolite of BD, have been conducted on blood samples from all participants in this second Czech study. Any adduct that may have been present was below the limits of quantitation (LOQ) for this assay for all samples, indicating that production of this important BD metabolite in humans is below levels produced in both mice and rats exposed to as little as 1.0 ppm BD by inhalation (J.A. Swenberg, M.G. Bird, R.J. Lewis, Future directions in butadiene risk assessment, Chem. Biol. Int. (2006), this issue). Results of assays for the HB-Val and THB-Val hemoglobin adducts are pending. HPRT mutations, determined by cloning assays, and multiple measures of chromosome level changes (sister-chromatid exchanges [SCE], aberrations determined by conventional methods and FISH) again showed no associations with BD exposures, confirming the findings of the initial study that these irreversible genotoxic changes do not arise in humans occupationally exposed to low levels of BD. Except for lower production of both urine metabolites in females, no female-male differences in response to BD exposures were detected in this study. As in the initial study, there were no significant genotype associations with the irreversible genotoxic endpoints. However, as in the first, differences in the metabolic detoxification of BD as reflected in relative amounts of the M1 and M2 urinary metabolites were associated with genotypes, this time both GST and EH.
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PMID:Molecular epidemiological studies in 1,3-butadiene exposed Czech workers: female-male comparisons. 1694 64

The crystal structure of human HPRT reveals the involvement of E196 side chain at the A-B dimer interface. Interference by valine substitution at this position (E196V), as identified in patients with Lesch-Nyhan disease, nearly abolishes enzymatic activity. Kinetic analysis of the active mutants (E196A, E196D, E196Q, and E196R) suggests that interaction between K68 and E196 side chains contributes to stabilization of cis-configuration during the catalytic cycle. The study also provides further insight into the role of A-B dimer interactions relating to K68 in the regulation of cis-trans isomerization that potentially governs the rate-limiting steps in the HPRT reaction.
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PMID:The role for glutamic acid at position 196 in human hypoxanthine phosphoribosyltransferase (HPRT) as investigated using site-directed mutagenesis. 1860 May 59


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