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)

Trans-stilbene oxide, trans-beta-methylstyrene 7,8-oxide, trans-beta-ethylstyrene 7,8-oxide, trans-beta-propylstyrene 7,8-oxide and 4-fluorochalcone oxide were investigated for genotoxic activity in bacterial and mammalian cells, in the absence of external xenobiotic-metabolising systems. All compounds strongly enhanced the frequency of sister-chromatid exchanges (SCE) in cultured human lymphocytes. None of them was mutagenic in Salmonella typhimurium (reversion of the his- strains TA98, TA100 and TA104). The limit of detection was 1/20,000 to 1/10(6) of the activity of the positive control, benzo[a]pyrene 4,5-oxide, depending on the compound and the bacterial strain. Trans-beta-methylstyrene 7,8-oxide and 4-fluorochalcone oxide were additionally tested for induction of SCE and gene mutations in the same target cells, namely Chinese hamster V79 cells. Their influence on the level of SCE was similar to that observed in human lymphocytes, whilst gene mutations (at the hprt locus) were not induced. The four investigated styrene oxide derivatives are known to be excellent substrates for a mammalian enzyme, cytosolic epoxide hydrolase (cEH). 4-Fluorochalcone oxide is a potent selective inhibitor of this enzyme and is structurally similar to the investigated styrene oxide derivatives. These properties of the test compounds however cannot explain the observed discrepancies in the results, since the genetic end point (SCE versus gene mutations) was decisive, and SCE were induced in cEH-proficient human lymphocytes as well as in cEH-deficient V79 cells.
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PMID:Some substrates and inhibitors of cytosolic epoxide hydrolase induce sister-chromatid exchanges in mammalian cells, but do not induce gene mutations in Salmonella typhimurium and V79 cells. 769 7

The genotoxic risks from exposure to polycyclic aromatic hydrocarbons (PAH) have long been recognized. Less well understood are the potential genotoxic risks of the atmospheric reaction products of this class of compounds. In this investigation, we have utilized several human cell genotoxicity assays to evaluate naphthalene, phenanthrene, and their atmospheric reaction products 1-nitronaphthalene, 2-nitronaphthalene, 1-hydroxy-2-nitronaphthalene, 2-hydroxy-1-nitronaphthalene, 1,4-naphthoquinone and 2-nitrodibenzopyranone. In addition, reaction products of naphthalene were generated in a 6700-1 Teflon environmental chamber, collected on a solid adsorbent, extracted and fractionated by normal-phase HPLC. Individual fractions were then analyzed using GC-MS, and tested for genotoxicity. Genotoxicity was determined using the human B-lymphoblastoid cell line, MCL-5, which expresses several transfected P450 and epoxide hydrolase genes. Mutagenicity was evaluated at both the heterozygous tk locus and the hemizygous hprt locus, permitting detection of both intragenic and chromosomal scale mutational events. Test compounds were also screened using the CREST modified micronucleus assay. Genotoxicity results indicate that 2-nitronaphthalene and 2-nitrodibenzopyranone possess greater mutagenic potency than their parent compounds, and interestingly, both compounds induced significant increases in mutation frequency at tk but not hprt. These results suggest a mechanistic difference in human cell response as compared to bacteria, where both compounds were previously shown to induce point mutations in the Salmonella reversion assay. The genotoxicity of 2-nitronaphthalene and 2-nitrodibenzopyranone in human cells, together with their high concentrations in ambient air relative to nitro-PAH directly emitted from combustion sources, emphasizes the need to consider atmospheric reaction products of PAH in genotoxicity assessments.
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PMID:Genotoxicity induced in human lymphoblasts by atmospheric reaction products of naphthalene and phenanthrene. 935 59