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)

In order to investigate the metabolic activation pathway of food-derived heterocyclic amines, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), cultured cell lines which stably expressed human cytochrome P4501A2 (CYP1A2) and N-acetyltransferases (NATs) were developed by the method of complementary DNA (cDNA) transfection. First, a cell line expressing CYP1A2, designated A2R-5, was established from the cell line CR-68, which was previously established by introducing NADPH-cytochrome P-450 reductase cDNA into Chinese hamster CHL cells. The expression of CYP1A2 in the transfected cells was confirmed by determining sensitivity to aflatoxin B1. As the next step, the A2R-5 as well as CR-68 cells were further transfected with human monomorphic NAT (NAT1) or polymorphic NAT (NAT2) cDNAs. The expression of NAT in the transfected cells was confirmed using p-aminobenzoic acid and sulfamethazine as substrates, while no activity was seen in parental CR-68 and A2R-5 cells. The cell line, ANP-25, which expressed both CYP1A2 and NAT2, was approximately 370- and 100-fold more sensitive to IQ and MeIQx, respectively, than parental CR-68 cells in cytotoxicity assays. There were no clear differences in sensitivity to both compounds among CR-68, A2R-5, and the cell lines which expressed NAT1 alone, NAT2 alone, and CYP1A2 plus NAT1. Mutagenicity of IQ and MeIQx at the hypoxanthine-guanine phosphoribosyltransferase locus was also detectable only in ANP-25 cells but not in A2R-5 or the cell line expressing CYP1A2 plus NAT1. From these results, it is proposed that both CYP1A2 and NAT2 (but not NAT1) are required for mutagenic activation of these compounds, implying that acetylator polymorphism may be an important risk factor in the carcinogenicity of these compounds.
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PMID:Stable expression of human CYP1A2 and N-acetyltransferases in Chinese hamster CHL cells: mutagenic activation of 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline. 801 61

Studies of mutation at the hypoxanthine phosphoribosyl transferase (hrpt) locus in human T-cells have the potential to elucidate the molecular basis of in vivo mutagenesis, reveal exposure dependent changes in ther background frequency of mutation, and provide knowledge on individual sensitivity. Styrene exposed lamination workers in Bohemia showed a significantly higher frequency of hprt mutant cells than Swedish control populations studied simultaneously. In a study of 47 healthy, non-smoking male bus maintenance workers exposed to diesel exhausts, soot and oil, and 22 unexposed controls, a significant correlation (P = 0.008) was obtained between the levels of aromatic DNA adducts and frequencies of hprt-mutant T-cells. In the group of workers with the highest exposure, subjects with glutathione S-transferase (GSTM1) deficiency showed significantly higher (P < 0.05) frequency of hprt mutant T-cells than GSTM1-positive subjects. The highest adduct levels were found in subjects with the combined genotype of GSTM1 and NAT2 deficiency (GSTM1-negative slow acetylators). These results indicate that GSTM1 and NAT2 genotypes may play a role in determining the individual levels of hprt mutation and DNA adducts. Using PCR-based screening methods, hprt mutations have been classified in 462 T-cell clones from 43 subjects in this study population. Deletions were found in 3% of the mutants, coding errors in 81% and splice mutations in 17%. Transitions and transversions were equally common, and all types of base substitutions were detected.
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PMID:Analysis of mutation at the hprt locus in human T lymphocytes. 859 72

Molecular epidemiology is a new and evolving area of research, combining laboratory measurement of internal dose, biologically effective dose, biologic effects, and influence of individual susceptibility with epidemiologic methodologies. Biomarkers evaluated were selected according to basic scheme: biomarkers of exposure--metabolites in urine, DNA adducts, protein adducts, and Comet assay parameters; biomarkers of effect--chromosomal aberrations, sister chromatid exchanges, micronuclei, mutations in the hypoxanthine-guanine phosphoribosyltransferase gene, and the activation of oncogenes coding for p53 or p21 proteins as measured on protein levels; biomarkers of susceptibility--genetic polymorphisms of genes CYP1A1, GSTM1, GSTT1, NAT2. DNA adducts measured by 32P-postlabeling are the biomarker of choice for the evaluation of exposure to polycyclic aromatic hydrocarbons. Protein adducts are useful as a biomarker for exposure to tobacco smoke (4-aminobiphenyl) or to smaller molecules such as acrylonitrile or 1,3-butadiene. Of the biomarkers of effect, the most common are cytogenetic end points. Epidemiologic studies support the use of chromosomal breakage as a relevant biomarker of cancer risk. The use of the Comet assay and methods analyzing oxidative DNA damage needs reliable validation for human biomonitoring. Until now there have not been sufficient data to interpret the relationship between genotypes, biomarkers of exposure, and biomarkers of effect for assessing the risk of human exposure to mutagens and carcinogens.
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PMID:Molecular epidemiology studies on occupational and environmental exposure to mutagens and carcinogens, 1997-1999. 1069 23

2-Amino-3-methyl-9H-pyrido[2,3-b]indole (MeAalphaC) and some metabolites were investigated for mutagenicity in mammalian cell lines and bacterial strains engineered for the expression of human enzymes. MeAalphaC induced gene mutations (studied at the hprt locus) in Chinese hamster V79-derived cells co-expressing cytochrome (CYP) 1A2 and sulphotransferase (SULT) 1A1 even at a concentration of 30 nM, but was inactive in cells co-expressing CYP1A2 and N-acetyltransferase (NAT) 1 or 2. MeAalphaC, tested in the presence of rat liver post-mitochondrial fraction, showed strongly enhanced mutagenicity in a Salmonella typhimurium strain expressing human SULT1A1 compared with the control (recipient) strain TA1538/1,8-DNP (deficient in endogenous acetyltransferase). Mutagenicity was also enhanced, although to a lesser extent, when NAT2 was expressed in the latter strain. The metabolite, 2-hydroxylamino-3-methyl-9H-pyrido[2,3-b]indole (N-OH-MeAalphaC) was a direct mutagen to strains TA1538 and TA1538/ 1,8-DNP. This mutagenicity was strongly enhanced in corresponding strains expressing SULT1A1. A moderate enhancement was observed when SULT1A2, SULT1B1, SULT1C2 or NAT2 were expressed in strain TA1538. The remaining enzymes studied (SULT1A3, 1C1, 1E1, 2A1, 2B1a, 2B1b, 4A1 and NAT1) did not indicate any activation of N-OH-MeAalphaC. Preliminary mutagenicity experiments in SULT-expressing S.typhimurium strains were conducted with other hydroxylated metabolites of MeAalphaC. The phenols, 6- and 7-hydroxy-MeAalphaC, were inactive under the conditions studied. The benzylic alcohol, 2-amino-3-hydroxymethyl-9H-pyrido[2,3-b]indole, was mutagenic in a strain expressing SULT1A1, but its activity was much weaker than that of N-OH-MeAalphaC. Thus, N-hydroxylation (e.g. mediated by CYP1A2) and sulpho conjugation (primarily mediated by SULT1A1) was the dominating activation pathway of MeAalphaC in model systems engineered for human enzymes. Some other SULT forms as well as NAT2 were also capable of activating N-OH-MeAalphaC, although with much lower efficiency than SULT1A1. Another minor activation pathway involved benzylic hydroxylation followed by sulpho conjugation by SULT1A1.
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PMID:Bioactivation of the heterocyclic aromatic amine 2-amino-3-methyl-9H-pyrido [2,3-b]indole (MeAalphaC) in recombinant test systems expressing human xenobiotic-metabolizing enzymes. 1472 82