Identification of Soluble Epoxide Hydrolase Inhibitors from the Seeds of Passiflora edulis Cultivated in Vietnam

Soluble epoxide hydrolases (sEH) are enzymes present in all living organisms, metabolize epoxy fatty acids to 1,2-diols. sEH in the metabolism of polyunsaturated fatty acids plays a key role in inflammation. In addition, the endogenous lipid mediators in cardiovascular disease are also broken down to diols by the action of sEH that enhanced cardiovascular protection. In this study, sEH inhibitory guided fractionation led to the isolation of five phenolic compounds trans-resveratrol (1), trans-piceatannol (2), sulfuretin (3), (+)-balanophonin (4), and cassigarol E (5) from the ethanol extract of the seeds of Passiflora edulis Sims cultivated in Vietnam. The chemical structures of isolated compounds were determined by the interpretation of NMR spectral data, mass spectra, and comparison with data from the literature. The soluble epoxide hydrolase (sEH) inhibitory activity of isolated compounds was evaluated. Among them, trans-piceatannol (2) showed the most potent inhibitory activity on sEH with an IC₅₀ value of 3.4 µM. This study marks the first time that sulfuretin (3) was isolated from Passiflora edulis as well as (+)-balanophonin (4), and cassigarol E (5) were isolated from Passiflora genus.

Interactions Between Bisphenol A Exposure and GSTP1 Polymorphisms in Childhood Asthma

PURPOSE: Bisphenol A (BPA) exposure may increase the risk of asthma. Genetic polymorphisms of oxidative stress-related genes, glutathione S-transferases (GSTM1, GSTP1), manganese superoxide dismutase, catalase, myeloperoxidase, and microsomal epoxide hydrolase may be related to BPA exposure. The aim is to evaluate whether oxidative stress genes modulates associations of BPA exposure with asthma. METHODS: We conducted a case-control study comprised of 126 asthmatic children and 327 controls. Urine Bisphenol A glucuronide (BPAG) levels were measured by ultra-performance liquid chromatography/tandem mass spectrometry, and genetic variants were analyzed by a TaqMan assay. Information on asthma and environmental exposure was collected. Analyses of variance and logistic regressions were performed to determine the association of genotypes and urine BPAG levels with asthma. RESULTS: BPAG levels were significantly associated with asthma (adjusted odds ratio [aOR], 1.29 per log unit increase in concentration; 95% confidence interval [CI], 1.081.55). Compared to the GG genotype, children with a GSTP1 AA genotype had higher urine BPAG concentrations (geometric mean [standard error], 12.72 [4.16] vs 11.42 [2.82]; P=0.036). In children with high BPAG, the GSTP1 AA genotype was related to a higher odds of asthma than the GG genotype (aOR, 4.84; 95% CI, 1.0223.06). CONCLUSIONS: GSTP1 variants are associated with urine BPA metabolite levels. Oxidative stress genes may modulate the effect of BPA exposure on asthma.

Gene variance in microsomal epoxide hydrolase and the susceptibility of coal workers' pneumoconiosis / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To explore whether the tagging single nucleotide polymorphisms (SNPs) within EPHX1 gene were involved in the genetic susceptibility to coal worker's pneumoconiosis (CWP) by case-control study.</p><p><b>METHODS</b>This study consisted of 697 CWP patients and 694 controls. All the subjects were Han Chinese, underground coal miners and recruited from coal mines of Xuzhou Mining Business Group Co Ltd.. The venous blood samples were obtained from all subjects and extracted genome DNA from the isolated leucocytes. Three SNPs were selected from the HapMap and the genotyping was done by the TaqMan method with the ABI 7900HT Real Time PCR system.</p><p><b>RESULTS</b>The Single SNP analyses showed that the genotype frequencies of EPHX1 (rs2234922) was significantly associated with decreased risk of CWP under co-dominant model (OR = 0.22, 95% CI = 0.06~0.79, P = 0.020), recessive model (OR = 0.23, 95% CI = 0.06~0.82, P = 0.023), and addictive model (OR = 0.75, 95% CI = 0.58~0.96, P = 0.022). The further stratification analysis showed that the risk of CWP will significantly decreased in non-smoking groups (OR = 0.10, 95% CI = 0.01~0.83, P = 0.033).</p><p><b>CONCLUSIONS</b>Our results suggest that individuals with the EPHX1 (rs223492) GG genotype was associated with a dereased risk of CWP, and it has a protective effect on the developing CWP.</p>

Study on the association between leukotriene A4 hydrolase gene polymorphism and ischemic stroke / 中华流行病学杂志

<p><b>OBJECTIVE</b>To investigate the association between polymorphism of leukotriene A4 hydrolase (LTA4H) gene among ischemic stroke patients and the related subtypes in the discordant sib pairs.</p><p><b>METHODS</b>Families including ischemic stroke patients and their siblings were recruited. Four single nucleotide polymorphisms (SNPs) of LTA4H as rs2072512, rs2540489, rs2540500 and rs6538697 were selected. Generalized estimating equation (GEE) was used to adjust for in-family correlation in the analysis of discordant sib pairs. Conditional logistic regression model and family based association test (FBAT) were both used to test the associations of LTA4H gene with ischemic stroke and its subtypes.</p><p><b>RESULTS</b>In total, data from 356 discordant sib pairs from 234 ischemic stroke patient pedigrees were analyzed. Results of GEE showed that hypertension, diabetes mellitus and hyperlipoidemia were associated with ischemic stroke. According to the association test results, rs2540489 G allele was found to be associated with ischemic stroke, both in the additive model (OR = 0.62, 95% CI: 0.41-0.94) and in the recessive model (OR = 0.48, 95% CI: 0.23-1.02). For two main ischemic stroke subtypes, rs2540489 G allele was found to be associated with large-artery atherosclerosis stroke in the additive model (OR = 0.48, 95% CI: 0.24-0.95) and in the recessive model (OR = 0.25, 95% CI: 0.07-0.93). After adjusting age, sex and other factors, the associations mentioned above, still existed.</p><p><b>CONCLUSION</b>rs2540489 polymorphism in LTA4H gene seemed to be associated with large-artery atherosclerosis stroke.</p>

Impact of six genetic polymorphisms on Warfarin maintenance dose variation in Chinese Han population / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To evaluate the effect of VKORC1, CYP2C9, GGCX, PROC, EPHX1 and CYP4F2 gene polymorphisms on Warfarin maintenance dose variation in Chinese Han Population.</p><p><b>METHODS</b>Four hundred eighty-eight patients with prosthetic heart valves, atrial fibrillation or pulmonary thromboembolism and achieved stable Warfarin dose were enrolled. TaqMan probe or direct sequencing were used to genotype Y9VKORC1, CYP2C9, GGCX, EPHX1 and CYP4F2 gene polymorphisms. Demographic characteristics, stable therapeutic dose of Warfarin and concomitant medications were collected for all patients. The effect of VKORC1, CYP2C9, GGCX, PROC, EPHX1 and CYP4F2 gene polymorphisms, demographic characteristics and concomitant medications on Warfarin daily maintenance dose were analyzed with statistical method.</p><p><b>RESULTS</b>VKORC1 and CYP2C9 gene polymorphisms could explain more than 50% Warfarin maintenance dose variation in recruited patients, while CYP4F2 gene polymorphisms could only explain 1%. GGCX, PROC and EPHX1 gene polymorphisms had no impact no Warfarin maintenance dose. VKORC1 and CYP2C9 gene polymorphisms have a greater impact on Warfarin maintenance dose compared with demographic characteristics and concomitant medications.</p><p><b>CONCLUSION</b>VKORC1 and CYP2C9 gene polymorphisms have a significant impact on Warfarin maintenance dose in Chinese Han population.</p>

Pinocembrin protects rats against cerebral ischemic damage through soluble epoxide hydrolase and epoxyeicosatrienoic acids / 中国天然药物

AIM@#To investigate the relationship between cerebroprotection of pinocembrin and epoxyeicosatrienoic acids (EETs) and their regulating enzyme soluble epoxide hydrolase (sEH).@*METHODS@#Rats underwent middle cerebral artery occlusion (MCAO) to mimic permanent focal ischemia, and pinocembrin was administrated via tail vein injection at 10 min, 4 h, 8 h and 23 h after MCAO. After 24 MCAO, rats were re-anesthetized, and the blood and brain were harvested and analyzed.@*RESULTS@#Pinocembrin displayed significant protective effects on MCAO rats indicated by reduced neurological deficits and infarct volume. Importantly, co-administration of 0.2 mg·kg(-1) 14, 15-EEZE, a putative selective EET antagonist, weakened the beneficial effects of pinocembrin. 14, 15-EET levels in the blood and brain of rats after 24 h MCAO were elevated in the presence of pinocembrin. In an assay for hydrolase activity, pinocembrin significantly lowered brain sEH activity of MCAO rats and inhibited recombinant human sEH activity in a concentration-dependent manner (IC50, 2.58 μmol·L(-1)). In addition, Western blot and immunohistochemistry analysis showed that pinocembrin at doses of 10 mg·kg(-1) and 30 mg·kg(-1) significantly down-regulated sEH protein in rat brain, especially the hippocampus CA1 region of MCAO rats.@*CONCLUSION@#Inhibiting sEH and then increasing the potency of EETs may be one of the mechanisms through which pinocembrin provides cerebral protection.

Influence of genetic polymorphisms of epoxide hydrolase 1 on metabolism of styrene in body / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To investigate the role of genetic polymorphisms of epoxide hydrolase 1 (EPHX1) in the metabolism of styrene in vivo.</p><p><b>METHODS</b>Fifty-six styrene-exposed workers, who worked in the painting workshop of an enterprise for manufacturing glass fiber-reinforced plastic yachts in Shandong Province, China for over one year and were protected in approximately the same way, were selected as study subjects. The 8-hour time-weighted average concentration (8 h-TWA) of styrene and the concentrations of mandelic acid (MA) and phenyl glyoxylic acid (PGA) as urinary metabolites were measured. The genetic polymorphisms of EPHX1 were detected by polymerase chain reaction-restriction fragment length polymorphism analysis.</p><p><b>RESULTS</b>The urinary concentrations of MA and PGA were 177.25±82.36 mg/g Cr and 145.91±69.73 mg/g Cr, respectively, and the 8 h-TWA of styrene was 133.28±95.81 mg/m3. Urinary concentrations of MA and PGA were positively correlated with 8 h-TWA of styrene (R=0.861, P < 0.05; R=0.868, P < 0.05). The subjects were divided into high-exposure group (8 h-TWA >50 mg/m(3)) and low-exposure group (8 h-TWA ≤ 50 mg/m(3), and in the two groups, the urinary concentrations of MA and PGA were significantly higher in the individuals carrying high-activity genotypes of EPHX1 than in those carrying low-activity genotypes of EPHX1 (P < 0.05).</p><p><b>CONCLUSION</b>Genetic polymorphisms of EPHX1 play an important role in the metabolic process of styrene in vivo.</p>

Soluble epoxide hydrolase inhibitor t-AUCB ameliorates ox-LDL induced conversion of macrophages into foam cells through activating the PPARγ-ABCA1 pathway / 中华心血管病杂志

<p><b>OBJECTIVE</b>To observe the effects of soluble epoxide hydrolase inhibitor t-AUCB on foam cell formation and cholesterol efflux in macrophage.</p><p><b>METHODS</b>Mouse macrophages RAW264.7 were cultured and stimulated with ox-LDL (80 µmol/L) in the absence (group A) or presence of t-AUCB (1, 10, 50, 100 µmol/L, group B) or t-AUCB (100 µmol/L) pretreated with PPARγ antagonist GW9662 (5 µmol/L, group C). The foam cell was identified by oil red O staining. The cholesterol efflux rates of (3)H-cholesterol in cells were measured by liquid scintillation counter. mRNA and protein expressions of ABCA1 were detected by real-time PCR or Western blot, respectively.</p><p><b>RESULTS</b>Oil red O staining showed that t-AUCB (100 µmol/L) significantly inhibited foam cell formation which could be significantly reversed by GW9662 (all P < 0.05). t-AUCB dose-dependently increased cholesterol efflux rates in mouse macrophage [(5.91 ± 0.18)% in group A, (7.03 ± 0.33)%, (8.05 ± 0.32)%, (9.04 ± 0.14)%, (10.06 ± 0.85)% in 1, 10, 50, 100 µmol/L t-AUCB groups, all P < 0.05 vs. group A], which could be reversed by pretreatment with GW9662 [(6.33 ± 0.15)% in 100 µmol/L t-AUCB + GW9662 group].t-AUCB also upregulated ABCA1 mRNA and protein expressions in a dose-dependent manner which could be significantly attenuated by pretreatment with GW9662.</p><p><b>CONCLUSION</b>t-AUCB could inhibit foam cell formation by improving cholesterol efflux through activating PPARγ-ABCA1 pathway in macrophage.</p>

Association analysis of polymorphisms of metabolizing enzyme genes with chronic benzene poisoning based on logistic regression and multifactor dimensionality reduction / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To explore the association of polymorphisms of metabolizing enzyme genes with chronic benzene poisoning (CBP) comprehensively by case-control design.</p><p><b>METHODS</b>152 CBP patients and 152 workers occupationally exposed to benzene without poisoning manifestations were investigated. 30 single nucleotide polymorphisms (SNPs) in 13 genes such as CYP2E1 were tested by PCR-RFLP, sequencing approaches. Logistic regression model was used to detect main effects and 2-order interaction effects of gene and/or environment. Multifactor dimensionality reduction (MDR) was used to detect high-order gene-gene or gene-environment interactions.</p><p><b>RESULTS</b>Based on logistic regression, the main effects of GSTP1 rs947894, EPHX1 rs1051740, CYP1A1 rs4646903, CYP2D6 rs1065852 and rs1135840 were found to be significant (P < 0.05) while the confounding factors of sex, cigarette smoking, alcohol consumption and the intensity of benzene exposure were controlled. EPHX1 rs1051740 might be associated with CBP (P = 0.06). There existed 3 types of interactions were as followed: interactions of GSTP1 rs947894 with alcohol consumption, CYP2E1 rs3813867 with EPHX1 rs3738047, EPHX1 rs3738047 with alcohol consumption(P < 0.05), while the main effects of CYP2E1 rs3813867 and EPHX1 rs3738047 were not significant (P > 0.05). The other SNPs did not show any significant associations with CBP. According to MDR, a 3-order interaction with the strongest combined effect was found, i.e. the 3-factor combination of CYP1A1 rs4646903, CYP2D6 rs1065852 and CYP2D6 rs1135840.</p><p><b>CONCLUSION</b>Gene-gene, gene-environment interactions are important mechanism to genetic susceptibility of CBP.</p>

Relationship between EPHX2 gene polymorphism and essential hypertension in Kazaks and Hans in Xinjiang / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the association between rs751141 gene polymorphisms in EPHX2 gene and essential hypertension in Kazak and Han in Xinjiang.</p><p><b>METHODS</b>A total of 267 essential hypertensive patients in Kazaks, 368 essential hypertensive patients in Hans, 284 normotensive controls in Kazaks and 348 normotensive controls in Hans were enrolled in this study. TaqMan assay was used to detect the rs751141 G/A gene polymorphisms of EPHX2 gene.</p><p><b>RESULTS</b>The rs751141 G/A genotype frequencies for GA + AA genotypes was 40.2 percent in essential hypertensive subjects and 52.0 percent in control subjects in Hans, respectively. The genotype frequencies were significant difference between the two groups in Hans in Xinjiang (P < 0.01). The rs751141G/A gene polymorphism had no significant difference between essential hypertensive patients and normotensive controls in Kazaks in Xinjiang (P > 0.05).</p><p><b>CONCLUSION</b>The essential hypertension in Kazaks in Xinjiang is not associated with rs751141G/A gene polymorphism of EPHX2 gene, but the essential hypertension in Hans in Xinjiang is associated with rs751141G/A allele gene polymorphism of EPHX2 gene. A type of rs751141 allele gene polymorphism may be the independent protective factor of essential hypertension in Hans in Xinjiang.</p>

Impact of five genetic polymorphisms on inter-individual variation in warfarin maintenance dose / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the effect of genetic polymorphisms in VKORC1, CYP2C9, GGCX, EPHX1, APOE genes on inter-individual variation in warfarin maintenance dose.</p><p><b>METHODS</b>Two hundred and forty-nine patients with stable warfarin dose were enrolled in this study, and the clinical data and blood samples of the patients were collected. Genotypes for the 5 genes were determined by using PCR and denaturing high performance liquid chromatography (DHPLC) assay. The warfarin maintenance doses were compared among patients with different genotypes of the 5 genes, and a warfarin stable dosing algorithm was derived based on genetic and non-genetic factors.</p><p><b>RESULTS</b>Of the 5 genes, VKORC1, CYP2C9 and GGCX were associated with warfarin stable dose. The multiple linear regression analysis indicated that VKORC1, CYP2C9 and GGCX genes, age and weight, had significant influence on inter-individual variation in warfarin stable dose, which contributed 30.2%, 22.8%, 1.5%, 4.7% and 6.7% respectively. The warfarin stable dosing algorithm acquired from the optimal regression model could explain 57.8% variation in warfarin dose.</p><p><b>CONCLUSION</b>This study suggested that genetic factors are the major determinants of the warfarin maintenance dose, and warfarin stable dosing algorithm may be useful for helping clinicians to prescribe warfarin with greater safety and efficiency.</p>

Effect of soluble epoxide hydrolase inhibitor on the function of endothelial progenitor cells in patients with coronary heart disease / 中南大学学报(医学版)

OBJECTIVE@#To investigate the effect of soluble epoxide hydrolase inhibitor (sEHi) tAUCB on the function of endothelial progenitor cells (EPCs) and expression of vascular endothelial growth factor (VEGF) in EPCs in patients with coronary heart disease (CHD).@*METHODS@#Mononuclear cells, from the peripheral blood of CHD patients, were isolated by ficoll density gradient centrifugation and cultured. After 7 days of culture in vitro, EPCs were identified by double staining and flow cytometry. EPCs were then stimulated by 0, 10(-6), 10(-5), and 10(-4) mol/L of tAUCB for 24 h. Migration assay was performed in transwell chamber and tube formation assay was performed by Matrigel-Matrix in vitro model. The expression of VEGF in EPCs was measured by Western blot. EPCs from age and gender matched healthy subjects were also cultured as controls.@*RESULTS@#The migration and tube formation activities of EPCs from CHD patients were obviously damaged compared with those from healthy controls (P<0.05). The tAUCB could dose-dependently increase the migration and tube formation activities and increase the expression of VEGF in EPCs compared with those from CHD patients without treatment. The 10(-6) mol/L tAUCB increased those activities of EPCs and the expression of VEGF with statistical difference.@*CONCLUSION@#sEHi can positively modulate the function of EPCs from CHD patients, suggesting the potential predictive significance of sEHi in the therapy of CHD.

QSAR, docking studies and pharmacophore identification of phenylmethyl phenoxy propyl amino propanoic acid derivatives as leukotriene A4 hydrolase inhibitors / 药学学报

The enzyme leukotriene A4 (LTA4) plays an important role as precursor of slow reactive substances as LTC4, LTD4, and LTE4. It is an attractive target for molecular modeling and QSAR study. Our effort is mainly focused on exploring the SAR for inhibitors of the LTA4 hydrolase through docking study, pharmacophore modeling and molecular descriptor study. The binding of these small molecules on LTA4 hydrolase enzyme was described by the models developed on 2D molecular descriptors, with good predictive power (39 compounds, 6 descriptors, r2 0.98, SEE 0.167, F-value 268.53, q2 0.90, r2 adj 0.97, P-value < 0.0001, SD of residuals 0.15). Docking studies were employed to presume the probable binding conformation of these analogues and exploring the SAR for the compounds. The novel pharmacophore represents the ligand features that are involved in interactions with the target protein, as well as the space around the ligand occupied by the protein. The efforts are aimed to discover the SAR for the inhibitors of LTA4 hydrolase through techniques of QSAR, docking and pharmacophore.

High-throughput screening of human soluble epoxide hydrolase inhibitors / 药学学报

To screen potential human soluble epoxide hydrolase (hsEH) inhibitors, a high-throughput screening model in 384-well microplate with total volume of 50 microL was established. Recombinant hsEH was cloned and expressed in E. coli. and its specific substrate PHOME was synthesized. The HTS model was based on fluorescence analysis with enhanced sensitivity and specificity (Z' = 0.65). A total of 47 360 samples (including 25 040 compounds and 22 320 natural products) were screened, of which 950 samples with inhibition greater than 80% were selected for further rescreening. Finally, two compounds with high inhibitory activity were identified, whose IC50 value were 8.56 and 4.31 micromol x L(-1), separately. The results indicated that the method was stable, sensitive, reproducible and also suitable for high-throughput screening.

Engineering the enantioselectivity of biocatalysts / 生物工程学报

Wild-type biocatalysts usually show high activity and selectivity towards their native substrates. Since non-native substrates are often used in synthetically useful biocatalytic transformations, it is necessary to engineer enzymes for improved activity, stability and selectivity (chemo-, regio- and stereoselectivity). Herein we give an overview of the recent advances in engineering the enantioselectivity of biocatalysts, with an aim to stimulate further development of this important field in China.

Controlling arachidonic acid metabolic network: from single- to multi-target inhibitors of key enzymes / 药学学报

Inflammatory diseases are common medical conditions seen in disorders of human immune system. There is a great demand for anti-inflammatory drugs. There are major inflammatory mediators in arachidonic acid metabolic network. Several enzymes in this network have been used as key targets for the development of anti-inflammatory drugs. However, specific single-target inhibitors can not sufficiently control the network balance and may cause side effects at the same time. Most inflammation induced diseases come from the complicated coupling of inflammatory cascades involving multiple targets. In order to treat these complicated diseases, drugs that can intervene multi-targets at the same time attracted much attention. The goal of this review is mainly focused on the key enzymes in arachidonic acid metabolic network, such as phospholipase A2, cyclooxygenase, 5-lipoxygenase and eukotriene A4 hydrolase. Advance in single target and multi-targe inhibitors is summarized.

Genetics of ischemic stroke

Stroke is the third leading cause of death and a major cause of disability worldwide. Most cases of ischemic stroke are attributable to hypertension and other risk factors, but in over 20% of cases, the cause is unknown. Recent research has implicated some novel genes in the etiology of ischemic stroke, including genes for soluble epoxide hydrolase [sHE], 5-lipoxygenase activating protein [FLAP] and phosphodiesterase 4D [PDE4D]. Moreover, thrombophilic states such as prothrombin G20210A mutation and factor V Leiden are now known to cause arterial stroke as well as venous thrombosis. Meanwhile, the recent availability of enzyme replacement therapy for Fabry disease and the proven benefits of regular blood transfusion in certain patients with sickle cell disease have greatly altered the outlook of these devastating inherited disorders. Thus, our understanding of the role of genetic factors in stroke raises the prospects for accurate assessment of future stroke risk among susceptible individuals, in whom early preventive measures may be life-saving. Further research into the genetics of stroke will clearly compliment ongoing national and international efforts to reduce the global burden of stroke

The interaction between microsomal epoxide hydrolase polymorphisms and indoor pollution in non small cell lung cancer / 中华预防医学杂志

<p><b>OBJECTIVE</b>To determine the interaction between indoor air pollution and mEH gene polymorphisms.</p><p><b>METHODS</b>Blood samples from 222 non small cell lung cancer patients and 222 healthy people were characterized by PCR and PCR-RFLP methods. The interaction coefficients were determined through unconditional logistic regression model.</p><p><b>RESULTS</b>Significant differences in the positive rate of mEH-exon3 mutant and the heterozygote were found between case and control groups (chi(2) = 7.046, P = 0.030). But no significant difference was found in mEH-exon4 non-wild-type between groups (chi(2) = 2.674, P = 0.263). mEH-exon3 mutant (OR = 1.99; 95% CI = 1.21, 3.25) could significantly increase the risk of lung cancer. After adjusted by confounding variables, significant interactions were found between the use of coal-wall stove and the non-wild type mEH gene. The interaction coefficients were increased with the duration of exposure and quantity of coal consumed. The super multiplication models were established between non-wild type mEH gene and the exposure to soot or oil fume during cooking. The interaction coefficients were 2.75 and 7.34 respectively for exon3 and exon4. No interaction was found between non-wild type mEH gene and irritation of eye or throat during cooking.</p><p><b>CONCLUSION</b>Through the molecular epidemiological techniques, we confirmed indoor air pollution that caused by coal burning was a noticeable lung cancer risk factor. The interaction between the polymorphisms of mEH gene and the indoor air pollution plays an important role in the carcinogenesis of lung.</p>

Genetic polymorphisms of glutathione-S-transferase and microsomal epoxide hydrolase in acquired aplastic anemia

Glutathione-S-transferase [GST] and microsomal epoxide hydrolase [mEh] are detoxifing enzymes that modulate the effects of exposure to various environmental cytotoxic and genotoxic agents, including those associated with increased risk of acquired aplastic anemia [AAA]. The GST mu1 [GSTM1], GST the ta1 [GSTT1] and mEh genes have polymorphisms with functional alteration that could explain the interindividual risks for AAA. To determine the frequency of GST and mEh polymorphisms as a risk factor for the susceptibility, clinical severity and response to treatment in a group of Egyptian paediatric patients with AAA. GST and mEh genotypes were determined by multiplex-PCR and PCR-RFLP analysis respectively in 21 patients with AAA and 20 healthy matched control subjects. The mEh enzyme activities genotypes were assessed. The incidence of the GSTT1 null genotype was significantly higher in AAA patients compared with the controls [85.7% vs. 50%] [OR 2.8, 95% CI 1.1-7.8, p=0.01]. The incidence of the heterozygous arginine [Arg] 139 polymorphism in exon 4 of the mEh gene was significantly higher in AAA patients compared with the controls [61.9% vs. 20%], [OR 3.07; 95% CI, 1.23-7.7, p=0.005]. The incidence of the fast mEh activity genotype was significantly higher in AAA patients compared with the controls [33.3% vs. 15%] [OR 2.9; 95% CI, 1.09-8.9, p=0.03]. Most patients with normal functional phenotype responded significantly favorably to treatment than patients with abnormal enzyme activity [p=0.027]. Genetic polymorphisms in biotransformation enzymes: GSTT1-null genotype, mEh His/Arg polymorphism and fast putative functional activity could be considered as risk factors to develop AAA. Moreover, abnormal functional activity of mEh enzyme was associated with worse prognosis of the disease

EHPred: an SVM-based method for epoxide hydrolases recognition and classification / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

A two-layer method based on support vector machines (SVMs) has been developed to distinguish epoxide hydrolases (EHs) from other enzymes and to classify its subfamilies using its primary protein sequences. SVM classifiers were built using three different feature vectors extracted from the primary sequence of EHs: the amino acid composition (AAC), the dipeptide composition (DPC), and the pseudo-amino acid composition (PAAC). Validated by 5-fold cross tests, the first layer SVM classifier can differentiate EHs and non-EHs with an accuracy of 94.2% and has a Matthew's correlation coefficient (MCC) of 0.84. Using 2-fold cross validation, PAAC-based second layer SVM can further classify EH subfamilies with an overall accuracy of 90.7% and MCC of 0.87 as compared to AAC (80.0%) and DPC (84.9%). A program called EHPred has also been developed to assist readers to recognize EHs and to classify their subfamilies using primary protein sequences with greater accuracy.