Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have combined genetic, radiation-reduced somatic cell hybrid (RRH), fluorescent in situ hybridization (FISH), and physical mapping methods to generate a contig of overlapping YAC, PAC, and cosmid clones corresponding to > 3 continuous Mb in 11q13. A total of 15 STSs [7 genes (GSTP1, ACTN, PC, MLK3, FRA1, SEA, HNP36), 4 polymorphic loci (D11S807, D11S987, GSTP1, D11S913), 3 ESTs (D11S1956E, D11S951E, and W1-12191), and 1 anonymous STS (D11S703)], mapping to three independent RRH segregation groups, identified 26 YAC, 7 PAC, and 16 cosmid clones from the CGM, Roswell Park, CEPH Mark I, and CEPH MegaYAC YAC libraries, a 5 genome equivalent PAC library, and a chromosome II-specific cosmid library. Thirty-six Alu-PCR products derived from 10 anonymous bacteriophage lambda clones, a cosmid containing the polymorphic marker D11S460, or STS-positive YAC or cosmid clones were identified and used to screen selected libraries by hybridization, resulting in the identification of 19 additional clones. The integrity and relative position of a subset of clones was confirmed by FISH and were found to be consistent with the physical and RRH mapping results. The combination of STS and Alu-PCR-based approaches has proven to be successful in attaining contiguous cloned coverage in this very GC-rich region, thereby establishing for the first time the absolute order and distance between the markers: CEN-MLK3-(D11S1956E/D11S951E/W1-12191)-FRA1-D 11S460-SEA-HNP36/ D11S913-ACTN-PC-D11S703-GSTP1-D11S987-TEL.
...
PMID:A 3-Mb contig from D11S987 to MLK3, a gene-rich region in 11q13. 926 7

A comprehensive approach to biological monitoring of 44 workers occupationally exposed to styrene in a hand lamination plant was performed by using several end-points: styrene in workplace air, styrene in exhaled air, styrene in blood, DNA strand breaks (SBs) and oxidised bases in mononuclear leukocytes, chromosomal aberrations in lymphocytes, immune parameters and genotyping of polymorphic genes of some xenobiotic-metabolizing enzymes (CYP 1A1, EPHX, GSTM1 and GSTP1). We found a significantly higher number of DNA SBs, measured by a modified comet assay, in mononuclear leukocytes of the styrene-exposed workers compared with results from 19 unexposed controls (P<0.001). A fairly strong correlation was observed between SBs and years of exposure (P<0.001, r=0.545). The styrene-exposed workers also showed a significantly increased frequency of chromosomal aberrations (P<0.0001 for highly exposed group, P<0.004 for medium-exposed group, and P=0.0001 for low-exposed group). The proliferative response of T-lymphocytes stimulated with concanavalin A was significantly suppressed in people exposed to styrene (P<0.05). We recorded a significant increase of the percentage of monocytes in differential white blood cell counts in the exposed group (P<0.05). Using flow cytometry, we found an increased expression of adhesion molecules CD62L, CD18, CD11a, CD11b, CD49d and CD54 in the exposed workers as compared with the control group (P<0.05).
...
PMID:Biomonitoring of occupational exposure to styrene in a plastics lamination plant. 1051 98

To evaluate the influence of individual susceptibility factors on the level of polyaromatic (PAH) hydrocarbon DNA adducts and hypoxanthine guanine phosphoribosyl transferase (HPRT) mutants in peripheral lymphocytes, 70 coke-oven workers exposed to PAH were genotyped for four metabolic enzyme polymorphisms of potential importance in PAH metabolism. The examined genetic polymorphisms concerned glutathione S-transferases M1 (GSTM1; gene deletion; 96 workers), T1 (GSTT1; gene deletion), P1 (GSTP1; Ile-->Val substitution at codon 104 or Ile-->Val at codon 104 and Val-->Ala at codon 113), and microsomal epoxide hydrolase (EPHX; Tyr-->His substitution at codon 113 and His-->Arg at codon 139). The workers were classified in a high- and low-exposure group on the basis of urinary concentration of 1-pyrenol. The GSTM1 null genotype increased the number of DNA adducts in smoking coke-oven workers with high PAH exposure. DNA adducts were affected by PAH-exposure in non-smokers and in GSTM1 null smokers and by smoking in GSTM1 null individuals. In a multiple linear regression analysis, the interaction of the GSTM1 genotype was statistically significant (p = 0.04) with smoking (yes/no) and of borderline significance (p = 0.06) with PAH-exposure (high/low). As smoking also increased urinary 1-pyrenol, the genotype modification seemed to concern DNA adducts due to smoking rather than occupational exposure. GSTT1 positive individuals showed an elevated level of DNA adducts in comparison with GSTT1 null subjects (p = 0.04), and EPHX genotypes associated with slow hydroxylation reaction yielded a higher (p = 0.05) HPRT mutant frequency than fast EPHX genotypes; these findings were, however, based on small numbers of subjects and need to be clarified in further studies. In conclusion, our findings indicate that homozygous deletion of GSTM1 results in an increased sensitivity to genotoxic PAHs in tobacco smoke, which is seen as an increase in aromatic DNA adducts in blood mononuclear cells.
...
PMID:Influence of GSTM1, GSTT1, GSTP1, and EPHX gene polymorphisms on DNA adduct level and HPRT mutant frequency in coke-oven workers. 1063 83

This paper reviews studies published in the international scientific literature evaluating the influence of genetically based metabolic polymorphisms on biological indicators of genotoxic risk in environmental or occupational exposure. Exposures due to life style (i.e. diet or smoking) were not considered. Indicators are subdivided into internal dose indicators (concentration of the substance or its metabolites in biological fluids, urinary mutagenicity, adducts of hemoglobin, plasma proteins and DNA), and early biological effects (chromosome aberrations, sister chromatid exchanges, micronuclei, COMET assay, HPRT mutants). The metabolic genotypes (or phenotypes) examined by various authors are: ALDH2 (aldehyde dehydrogenase), CYP (P450 cytochrome) 1AI, CYP1A2, CYP2E1, CYP2D6, EPHX (epoxidohydrolase), NAT2 (N-acetyl transferase), NQO1 (NAD(P)H: kinone oxidoreductase), PON1 (paraoxonase), GST (glutathione S-transferase) M1, GSTT1 and GSTP1. In more than half the studies (52 out of 96), no influence of genotype was found in the biological indicator. This may be due either to the poor sensitivity of the indicator used, or to low exposure. In studies examining the effect of genotype on the indicator, the biological plausibility of the result was evaluated, i.e., whether the effect is consistent with the type of enzymatic activity expressed. Four studies reported not very reliable results and suggest either the unfavourable influence of genotype GSTM1 with high detoxifying activity, or enzymatic activity poorly involved in the metabolism of the xenobiotics in question (NAT2 in the case of PAH). As regards urinary metabolites of genotoxic agents, eight studies reported the modulating effect of genotype. The urinary excretion of mercapturic acids was greater in subjects with high GST activity. In exposure to PAH, urinary 1-pyrenol and PAH metabolites turn out to be significantly influenced by genotypes CYP1A1 or GSTM1 null; in exposure to aromatic amines, the influence of NAT2 on exposure indicators (levels of acetylated and non-acetylated metabolites) was confirmed. Exposure to benzene led to an increase in t-t-MA in some genotypes, although experimental verification is still necessary. As regards urinary mutagenicity, the effect of genotype GSTM1 null is reported, and of the same genotype combined with NAT2 slow, in non-smoking individuals subjected to high exposure to PAH and in cigarette-smoking/coke-oven workers. Lastly, the determination of urinary metabolites in monitoring exposure to genotoxic substances, provides sufficient evidence that genetically based metabolic polymorphisms must be taken into account in the future. There is still little evidence regarding the importance of genotype on the level of protein adducts in environmental and occupational exposure. A relatively large number of publications (22) dealt with DNA adduct levels in PAH exposure. In 18 studies, the biological indicator clearly increases with respect to values in control subjects. Of these studies, seven reported the influence of GSTM1 null on DNA adducts and, of the five studies which also examined genotype CYP1A1, four reported the influence on DNA adduct level of genotype CYP1A1, alone or in combination with GSTM1 null. It therefore seems as if the unfavourable association for the activating/detoxifying metabolism of PAH is a risk factor for the formation of PAH-DNA adducts. Most publications (25 out of 41; 61%) dealing with metabolic polymorphisms in effect indicators (cytogenetic markers, COMET assay, HPRT mutants) did not report any increase in the indicator due to exposure to the genotoxic agents studied. These indicators of genotoxic damage, including mainly the frequency of HPRT mutants (100%), Mn (90%) and the COMET assay (67%), are not sufficiently sensitive in revealing exposure, confirming that they are not particularly suitable for measuring exposure to genotoxic substances in occupational or environmental exposures. It is therefore difficult to assess the influence of metabolic genotypes by means of this type of biological indicator. The few positive results reported for SCE in occupational studies mentioned the influence of genotype ALDH2, either alone or in combination with genotype CYP2E1 in exposure to CVM, or in combination with GSTM1 null in exposure to epichlorohydrin. For CA the results showed unfavourable combinations of genotypes CYP2E1, GSTM1 and PON1 in exposure to pesticides, and GSTM1 null in combination with NAT2 slow in exposure to urban air. All the remaining studies on the effect of genotype on biological indicators of cytogenetic damage reported negative results.
...
PMID:[Biomarkers of gentotoxic risk and metabolic polymorphism]. 1118 84

Polymerase chain reaction-restriction fragment length polymorphism based genotyping assays were used to determine the frequency of polymorphisms in CYP1A1 (3'-flanking region), CYP2E1 (5'-flanking region and intron 6), EPHX (exon 3 and exon 4), GSTM1 (deletion), GSTP1 (exon 5) and GSTT1 (deletion) in a group of 416 Czech individuals. A comprehensive overview of the methodology is also presented. We have found the following frequencies of mutated alleles: CYP1A1-m2, 0.097; CYP2E1-C, 0.077; CYP2E1-c2, 0.023; EPHX(exon 3)-His, 0.381; EPHX(exon 4)-Arg, 0.198; GSTM1-null, 0.51; GSTP1-Val, 0.3; GSTT1-null, 0.164. These values are similar to those presented in the majority of studies on European Caucasians, although a few cases of significant differences in the distribution of genotypes were found. These differences were most probably caused by methodological variations or statistical bias in the analyses of low numbers of samples in the control groups of some authors. Based on the results of EPHX genotyping, the activity of its protein product was deduced and the Czech population was divided into three subgroups with low, medium and high EPHX activity. We found that 43% of the Czech population would fall into the low, 44% into the medium and 13% into the high EPHX activity group. The data obtained may prove to be very useful for epidemiological studies on the influence of genetic polymorphisms of biotransformation enzymes on carcinogenesis or other environment-related diseases.
...
PMID:Genetic polymorphisms of biotransformation enzymes: allele frequencies in the population of the Czech Republic. 1119 82

Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of neoplasms with wide variation in histologic features, immunologic phenotype, molecular abnormalities, clinical presentation, and disease progression. New molecular techniques have significantly increased understanding about the molecular background for development of NHL and it has been possible to identify typical genetic abnormalities in specific NHL subtypes. Some of the genetic changes and alterations in predisposing genes related to NHL are reviewed in this article. The reviewed information suggests that it is of great importance to look for reliable diagnostic tools for screening of population groups to identify individuals at high risk of lymphomas. The follow up of interaction of various predisposing genes and environmental factors in lymphoma pathogenesis is of considerable public health importance as well. In a pilot study, polymerase chain reaction-restriction fragment length polymorphism based genotyping assays were used to determine the frequency of polymorphisms in genes coding for various biotransformation enzymes in a case-control study comprised of 147 patients with NHL and group of age- and sex-matched unrelated healthy Czech individuals. Preliminary statistical analyses showed no association of CYP1A1-m1/m2, CYP2E1-c1/c2, GSTM1null, and GSTT1null genotypes with incidence and status of NHL. On the other hand significant differences in distribution of genotypes of CYP2E1-intron 6, EPHX-exon 3, and GSTP1-exon 5 were observed between cases and controls. Thus it seems that study of co-segregation of particular genotypes of biotransformation enzymes with higher risk of lymphoproliferative disorders may prove to be very useful approach in elucidation of the etiology of malignancies of lymphoid origin.
...
PMID:Role of genetic factors in development and progression of non-Hodgkin's lymphomas. 1150 78

A comprehensive approach to evaluate genotoxic effects induced by styrene exposure was employed in 44 hand-lamination workers in comparison with 18 unexposed controls. The acquired data on single-strand breaks in DNA (SSBs), frequency of chromosomal aberrations and HPRT mutant frequency in peripheral blood lymphocytes were compared to the results on genotyping of some of the xenobiotic-metabolising enzymes (CYP1A1, CYP2E1, epoxide hydrolase and GSTM1, GSTP1 and GSTT1). Multifactorial regression analysis indicated that SSB in DNA were significantly associated with styrene exposure and with heterozygosity in CYP2E1 (5'-flanking region and intron 6; r(2)=0.614). The frequency of chromosomal aberrations (CA), as analysed by linear multiple regression analysis, significantly correlated with years of employment (P=0.004) and with combinations of epoxide hydrolase (EPHX) genotypes (exon 3, Tyr/His and exon 4, His/Arg), where individuals with low and medium activity EPHX genotypes exhibited higher frequencies of CA than those with high activity genotypes (P=0.044, r(2)=0.563). Moderately higher HPRT mutant frequencies were detected in styrene-exposed individuals (20.2 +/- 25.8 x 10(-6)) as compared to controls (13.3 +/- 6.3 x 10(-6)), but this difference was not significant. ANOVA (in the whole set of data) revealed that mutant frequencies at the HPRT gene were significantly associated with years of employment (F=6.9, P=0.0001), styrene in blood (F=10.1, P=0.0001), and heterozygosity in CYP2E1 (intron 6; F=13.5, P=0.0008) and GSTP1 (exon 5; F=3.6, P=0.038). In conclusion, our present data suggest that analysed biomarkers of DNA damage may be modulated by polymorphic CYP2E1, EPHX and GSTP1. In our study, styrene-specific DNA and haemoglobin adducts are under investigation. Completing these data with the results of genotyping of metabolising enzymes may provide a useful tool for individual genotoxic risk assessment.
...
PMID:Association between genetic polymorphisms and biomarkers in styrene-exposed workers. 1153 53

The role of polymorphic xenobiotic-metabolizing enzymes in the interindividual variability of phenylhydroxyethyl mercapturic acids (PHEMAs) was investigated in 56 styrene-exposed workers. Ambient monitoring was carried out using passive personal samplers (geometric mean, 157 mg/m3 8-h time-weighted average; geometric standard deviation, 2.90). Biomonitoring was based on mandelic acid and phenylglyoxylic acid in urine spot samples collected at the end of the work shift ("end-of-shift") and prior to the subsequent shift ("next morning"). Four PHEMA diastereoisomers, namely (R,R)-M1, (S,R)-M1, (S,R)-M2, and (R,R)-M2, were determined by HPLC/tandem mass spectrometry. The genotypes of glutathione S-transferases M1-1 (GSTM1), T1-1 (GSTT1) and P1-1 (GSTP1), and microsomal epoxide hydrolase (EPHX) were characterized by PCR-based methods. Workers bearing the GSTM1pos genotype showed PHEMA concentrations five and six times higher (in end-of-shift and next-morning samples, respectively) as compared to GSTM1null people. In GSTM1pos subjects, (R,R)-M1 was the main mercapturate affected by the GSTM1 status, accounting for 54 and 68% of total PHEMAs in end-of-shift and next-morning samples, respectively. Compared to GSTM1null, GSTM1pos subjects excreted more -M1 than -M2 and more (R,R)-M1 and (S,R)-M2 than (S,R)-M1 and (R,R)-M2 diastereoisomers. Thus, GSTM1-1 is the main isoenzyme catalyzing GSH-conjugation of styrene-7,8-oxide in humans and it seems to act in a regio- and stereoselective way. PHEMAs cannot be recommended as biomarkers of exposure to styrene, unless the GSTM1 genotype is considered in data interpretation. Their role as biomarkers of susceptibility deserves further studies.
...
PMID:Polymorphism of xenobiotic-metabolizing enzymes and excretion of styrene-specific mercapturic acids. 1159 31

A cross-sectional study was carried out on 48 workers exposed to styrene and 14 unexposed healthy controls in order to investigate the genotoxic potential of styrene exposure. DNA damage was assessed in peripheral blood leukocytes (WBCs) by the comet assay. Polymorphisms in glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) and the gene encoding microsomal epoxide hydrolase (EPHX) were characterized to assess their possible modifying role in styrene metabolism and subsequent DNA damage. Exposed workers showed significantly higher levels of DNA damage compared to controls. Among workers, the GSTM1 and GSTT1 polymorphisms significantly affected comet parameters. Subjects bearing a GSTM1pos genotype showed a significantly higher proportion of damaged nuclei compared to people lacking GSTM1-1 expression (GSTM1null), whereas GSTT1pos workers showed significantly lower DNA damage than GSTT1null individuals. Styrene-7,8-oxide (SO)-induced DNA damage was assessed in vitro in WBCs isolated from the healthy controls. A clear dose-response relationship at micromolar doses of SO was found for the whole group. WBCs collected from subjects bearing the homozygous wildtype GSTP1 genotype showed a significant protection compared to cells from subjects bearing at least one GSTP1 variant allele. The field survey confirms that styrene exposure is associated with increased DNA damage and indicates a modulating role for GSTM1 and GSTT1 genotypes. In vitro experiments suggest that the extent of SO-induced DNA strand breaks depends, at least in part, on interindividual differences in GSH-conjugation capabilities.
...
PMID:Genetic polymorphism of drug-metabolizing enzymes and styrene-induced DNA damage. 1271 79

Little is known about the impact of genetic variation on the genetic damage induced by urban air pollution or environmental tobacco smoke (ETS) in exposed populations. The levels of bulky DNA adducts ( 32P-postlabelling, nuclease P1 enrichment) and chromosomal aberrations were measured in lymphocytes of 194 non-smoking students living in the city of Athens, and the rural region of Halkida, Greece. In these individuals personal exposure to PAH was also measured. Furthermore, genetic polymorphisms were examined in cytochromes P450 1A1, 1B1, in the GSTM1, GSTP1 and GSTT1 as well as in microsomal epoxy hydrolase (EPHX) genes. Subjects with the CYP1*2A mutant genotype also suffering significant ETS exposure tended to exhibit higher adduct levels and % aberrant cells. In contrast, CYP1B1 polymorphisms seemed to have an impact on the DNA adduct levels only among individual with negligible ETS exposure. Subjects carrying both the CYP1*2A mutant genotype and the GSTM1 null genotype tended to have higher DNA adduct levels. A similar effect was also observed with the combined CYP1A1*2A/GSTP1 (Ile/Val) and the CYP1A1*2A/mEH "slow" polymorphisms. In both cases, the effect was more pronounced among subjects with higher levels of ETS exposure. Stepwise restriction of the observations to subjects characterised by (a) GSTP1 mutant, (b) GSTM1 null, (c) mEH "slow" (His139His) genotypes and (d) ETS exposure resulted in a significant trend of increasing DNA adduct levels only among individuals with at least one CYP1A1*2A mutated allele, illustrating the importance and complexity of gene-exposure and gene-gene interactions in determining the level of genotoxic damage on an individual levels.
...
PMID:Impact of phase I or phase II enzyme polymorphisms on lymphocyte DNA adducts in subjects exposed to urban air pollution and environmental tobacco smoke. 1509 73


1 2 3 4 5 Next >>

---