Huijuan Wang

Northwest University, Ch’ang-an, Shaanxi, China

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Publications (12)33.84 Total impact

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    ABSTRACT: 1. CYP1A2 is a highly polymorphic gene and CYP1A2 enzyme results in broad inter-individual variability in response to certain pharmacotherapies, while little is known about the genetic variation of CYP1A2 in Uyghur Chinese population. The aim of the present study was to screen Uyghur volunteers for CYP1A2 genetic polymorphisms. 2. We used DNA sequencing to investigate promoter, exons, introns, and 3' UTR of the CYP1A2 gene in 96 unrelated healthy Uyghur individuals. We also used SIFT (Sorting Intolerant From Tolerant) and PolyPhen-2 (Polymorphism Phenotyping v2) to predict the protein function of the novel non-synonymous mutation in CYP1A2 coding regions. 3. We identified 20 different CYP1A2 polymorphisms in the Uyghur Chinese population, including two novel variants (119A > G and 2410G > A). Variant 119A > G was predicted to be probably damaging on protein function by PolyPhen-2, by contrast, 2410G > A was identified as benign. The allele frequencies of CYP1A2*1A, *1B, *1F, *1G, *1J, *1M, *4, and *9 were 23.4%, 53.1%, 3.7%, 2.6%, 2.6%, 13.5%, 0.5%, and 0.5%, respectively. The frequency of *1F, a putative high inducibility allele, was higher in our sample population compared with that in the Caucasian population (p < 0.05). The most common genotype combinations were *1A/*1B (46.9%) and *1B/*1M (27.1%). 4. Our results provide basic information on CYP1A2 polymorphisms in Uyghur individuals and suggest that the enzymatic activities of CYP1A2 may differ among the diverse ethnic populations of the world.
    Xenobiotica 09/2015; DOI:10.3109/00498254.2015.1089367 · 2.20 Impact Factor
  • Xugang Shi · Li Wang · Shuli Du · Huijuan Wang · Tian Feng · Tianbo Jin · Longli Kang ·
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    ABSTRACT: Little is known about polymorphic distribution of pharmacogenes among ethnicities, including the Deng people. In this study, we recruited 100 unrelated, healthy Deng people and genotyped them with respect to 76 different single-nucleotide polymorphisms by the PharmGKB database. Our results first indicated that the polymorphic distribution of pharmacogenes of the Deng people is most similar to CHD, suggesting that Deng people have a closest genetic relationship with CHD. Our data will enrich the database of pharmacogenomics and provide a theoretical basis for safer drug administration and individualized treatment plans, promoting the development of personalized medicine.
    Biomarkers 07/2015; 20(5):1-12. DOI:10.3109/1354750X.2015.1068859 · 2.26 Impact Factor
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    ABSTRACT: Lung cancer is the leading cause of cancer-related deaths worldwide that result from the combined effected of smoking exposure and genetic susceptibility. CHRNA3, a nicotinic acetylcholine receptor gene, was associated with lung cancer risk. The aim of this study was to identify whether CHRNA3 polymorphisms increase lung cancer risk directly or indirectly through smoking behavior in the Chinese Han individuals. We conducted a case-control study including 228 individuals with lung cancer and 301 healthy individuals. Seventeen known SNPs within CHRNA3 were selected for genotyping. Odds ratios (OR) and 95 % confidence interval (CI) were calculated by unconditional logistic regression with adjustment for gender and age. Two SNPs (rs8042059 and rs7177514) showed a 1.54-fold (p = 0.036; 95 % CI = 1.03-2.32) and 1.52-fold (p = 0.043; 95 % CI = 1.01-2.27) increased risk for lung cancer in smokers, respectively. Rs8042059 also showed a significant association for variant genotypes (CA/AA) compared with the wild-type genotype (CC), with an OR = 1.84 (p = 0.042; 95 % CI, 1.02-3.33) in the dominant model. In addition, the haplotype analysis found that the haplotypes "TCAC" and "CTGT," composed of rs938682, rs12914385, rs11637630, and rs2869546, were associated with a 1.79-fold and 501-fold increased lung cancer risk, respectively. However, the polymorphisms of all SNPs were not significantly different between controls and cases among general or nonsmokers population. Rs8042059 and rs7177514 may increase lung cancer risk indirectly through smoking behavior in the Chinese Han population.
    Tumor Biology 02/2015; 36(7). DOI:10.1007/s13277-015-3149-0 · 3.61 Impact Factor
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    Xiaojie Xun · Huijuan Wang · Hua Yang · Hong Wang · Bo Wang · Longli Kang · Tianbo Jin · Chao Chen ·
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    ABSTRACT: Genetic variants of cleft lip and palate trans-membrane 1-like (CLPTM1L) genes in the p15.33 region of chromosome 5 were previously identified to influence susceptibility to lung cancer. We examined the association of single nucleotide polymorphisms (SNPs) in CLPTM1L genes with lung cancer and explored their potential effects on the relationship between environmental risk factors (smoking, drinking) and lung cancer in a Chinese Han population.We genotyped 9 single nucleotide polymorphisms (SNPs) of CLPTM1L in a case-control study with 228 lung cancer cases and 301 controls from northwest China. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression.We identified that the minor alleles of rs451360, rs402710, and rs31484 in CLPTM1L were associated with a 0.52-fold, 0.76-fold, and 0.70-fold decreased risk of lung cancer in allelic model analysis, respectively. In the genetic model analysis, we found rs402710 and rs401681 were associated with decreased lung cancer risk. Further stratification analysis showed that rs380286 displayed a significantly decreased lung cancer risk (OR = 0.65, P = 0.041) in the non-drinkers. In addition, Haplotype "GTTATCTGT" was found to be associated with decreased lung cancer risk (OR = 0.50, P = 0.033).Our results verified that genetic variants of CLPTM1L contribute to lung cancer susceptibility in the northwest Chinese Han population. Additionally, we found that consumption of alcohol may interact with CLPTM1L polymorphisms to contribute to overall lung cancer susceptibility.
    Medicine 12/2014; 93(28):e289. DOI:10.1097/MD.0000000000000289 · 5.72 Impact Factor
  • Huijuan Wang · Bobo Yang · Tingting Geng · Bin Li · Penggao Dai · Chao Chen ·
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    ABSTRACT: Gene transcription analysis in clinical tumor samples can help with diagnosis, prognosis, and treatment of cancers. We aimed to identify the optimal reference genes for reliable expression analysis in various tumor samples by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Using a one-step TaqMan-based qRT-PCR, 5 commonly used reference genes (ACTB, GAPDH, RPLPO, GUSB, and TFRC) and 10 anticancer drug-related genes (TYMS, RRM1, TUBB3, STMN1, TOP2A, EGFR, VEGFR2, HER2, ERCC1, and BRCA1) were analyzed in 327 tissues samples from lung, rectal, colon, gastric, esophageal, and breast tumors. According to the expression stability assessments obtained by using three programs (geNorm, NormFinder, and BestKeeper) and a comprehensive ranking method, the optimal reference genes for lung, gastric, esophageal, and breast tumors were RPLPO, GAPDH, ACTB, and ACTB, respectively. For rectal tumors, a combination of the 3 most stable genes (GUSB, ACTB, and RPLPO) was suitable for qRT-PCR, whereas for colon tumors, a combination of the 4 most stable genes (GAPDH, ACTB, GUSB, and RPLPO) was optimal for qRT-PCR. Based on the expression data of target genes normalized against selected reference genes, the principal component analysis revealed 4 expression patterns in the 6 different tissues. One pattern was observed in gastric, rectal, and colon tumor tissues, which are gastrointestinal tumors. Expressions in the breast, lung, and esophageal tissues were separately represented as one pattern. Our results could facilitate the practice of personalized cancer medicine based on the gene expression profile of the patients. Copyright © 2014. Published by Elsevier Inc.
    Experimental and Molecular Pathology 11/2014; 98(3). DOI:10.1016/j.yexmp.2014.10.014 · 2.71 Impact Factor
  • Huijuan Wang · Ting Bian · Tianbo Jin · Yong Chen · Aifen Lin · Chao Chen ·
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    ABSTRACT: Aim: 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan, is mainly eliminated hepatically through glucuronidation by UGT1A1 and UGT1A9 enzymes. This study comprehensively investigates the effects of UGT1A1 and UGT1A9 genetic polymorphism on SN-38 glucuronidation activity. Materials & methods: Genetic polymorphisms and combinational haplotypes of UGT1A1 and UGT1A9, SN-38 glucuronidation activities, and protein levels of UGT1A1 and UGT1A9 were determined using a set of over 45 Chinese livers. Results: UGT1A1 reduced function variants UGT1A1*6, *28, *60 and *1B exhibited additive effect. The number of UGT1A1 reduced function alleles was associated with decreased SN-38G formation rates and UGT1A protein levels. UGT1A9 I399C>T and UGT1A9*1b, which were highly linked, were associated with increased SN-38 glucuronidation activity and UGT1A protein levels. However, further analysis based on UGT1A9-1A1 haplotypes confirmed that their increased effect was partly due to their close linkage with UGT1A1 reduced function alleles. Conclusion: UGT1A1 genetic polymorphisms have a more important function in human liver SN-38 glucuronidation activity than UGT1A9. Original submitted 7 November 2013; Revision submitted 30 January 2014.
    Pharmacogenomics 04/2014; 15(6):785-798. DOI:10.2217/pgs.14.29 · 3.22 Impact Factor
  • Huijuan Wang · Raymond A Kim · Dongxu Sun · Yiwen Gao · Hao Wang · Juanli Zhu · Chao Chen ·
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    ABSTRACT: To comprehensively understand the effects of CYP2C19 genetic polymorphisms on inhibition-based drug-drug interactions (DDIs), 18 human CYP2C19 non-synonymous single-nucleotide polymorphic variants and the wild-type isoform (CYP2C19.1A) were expressed in yeast cells. Using a fluorescence-based high-throughput method, the kinetic constants of these variants, as well as the inhibition constants for 10 drugs, were determined. CYP2C19.5B and CYP2C19.6 showed no activity towards CEC (3-cyano-7-ethoxycoumarin) O-deethylation. CYP2C19.8, CYP2C19.9, CYP2C19.10, CYP2C19.16, CYP2C19.19, E122A and A161P* (an allele containing both A161P and I331V) exhibited significantly reduced catalytic activities compared with CYP2C19.1A. The inhibition assay showed that the CYP2C19 genotype significantly affected the in vitro drug inhibition potential. Although the effect on drug inhibition potential is genotype- and inhibitor-dependent, there was an obvious trend: drugs tended to exhibit higher IC₅₀ values (i.e. decreased inhibition potential) towards variants with reduced activity compared with variants with normal activity. This indicated that patients with reduced-function alleles may be less susceptible to CYP2C19-related DDIs. In this study, we provided the first in vitro evidence of CYP2C19 genotype-dependent effects on drug inhibition potential. This work greatly extends our understanding of the functional consequences of CYP2C19 genetic polymorphisms, and thus should prove valuable for CYP2C19 genotype-based therapy.
    Xenobiotica 06/2011; 41(9):826-35. DOI:10.3109/00498254.2011.582893 · 2.20 Impact Factor
  • Huijuan Wang · Ting Bian · Duan Liu · Tianbo Jin · Yong Chen · Aifen Lin · Chao Chen ·
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    ABSTRACT: Tegafur is primarily converted to 5-fluorouracil (5-FU) by CYP2A6 in the human liver to exert its antitumor effect. Our objective was to comprehensively investigate the effects of CYP2A6 genetic polymorphisms on tegafur bioactivation activity. Using a set of over 45 Chinese livers, the association between CYP2A6 genetic variations and 5-FU formation rates from tegafur, as well as CYP2A6 mRNA and protein levels, was determined. A total of 20 polymorphic variants and 20 haplotypes of CYP2A6 were identified. From genotype/haplotype-phenotype association tests, we demonstrated that CYP2A6*4 was the main allele responsible for the decreased 5-FU formation from tegafur and CYP2A6 expression in this population. By contrast, haplotype 14 (a novel CYP2A6*1B allele) was associated with increased microsomal 5-FU formation activity and CYP2A6 expression, and this may be attributed to the combined effects of three single variants (g.22C>T, g.1620T>C and a gene conversion in the 3´-UTR) included in this haplotype. We concluded that CYP2A6*4 and the novel CYP2A6*1B variant were the major genetic determinants of interindividual variability in 5-FU formation from tegafur in Chinese livers. Original submitted 2 November 2010; Revision submitted 3 December 2010.
    Pharmacogenomics 04/2011; 12(4):481-92. DOI:10.2217/pgs.10.202 · 3.22 Impact Factor
  • Huijuan Wang · Nianzhen An · Hao Wang · Yiwen Gao · Duan Liu · Ting Bian · Juanli Zhu · Chao Chen ·
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    ABSTRACT: CYP2C19 is a highly polymorphic enzyme that affects the metabolism of a wide range of therapeutic drugs. Almost all the identified alleles of CYP2C19 are derived from nonsynonymous single nucleotide polymorphisms (nsSNPs). The objective of this study was to functionally characterize 20 nsSNPs of CYP2C19, distributed throughout the entire coding region, most of which have not been thoroughly characterized. cDNAs of these variants were constructed and expressed in yeast cells. All variants had similar levels of apoprotein and holoprotein expression, except for CYP2C19.16 and D360N, which had significantly lower holoprotein levels than the wild-type (WT) CYP2C19 enzyme, and CYP2C19.5B, which showed only apoprotein. The activity of the CYP2C19 variants was investigated using two substrates, S-mephenytoin and omeprazole, and six different kinetic parameters were measured. CYP2C19.5B, CYP2C19.6, and CYP2C19.8 were found to be catalytically inactive. The entire dataset of the remaining 17 variants, together with the WT, was analyzed by multivariate analysis. This analysis indicated that CYP2C19.9, CYP2C19.10, CYP2C19.16, CYP2C19.18, CYP2C19.19, A161P, W212C, and D360N were substantially altered in catalytic properties in comparison with the WT, with each of these variants exhibiting either dramatically decreased catalytic activities or higher K(m) values. These results not only generally confirmed the function of previously reported variants but also identified additional reduced-function variants. These findings will greatly extend our understanding of CYP2C19 genetic polymorphisms in humans as well as facilitate the structure-function study of the CYP2C19 protein.
    Drug metabolism and disposition: the biological fate of chemicals 02/2011; 39(5):830-7. DOI:10.1124/dmd.110.037549 · 3.25 Impact Factor
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    ABSTRACT: Nonsynonymous single-nucleotide polymorphisms (nsSNPs) in cytochrome P450 (P450) genes may affect drug metabolism and drug-drug interactions (DDIs), potentially leading to adverse drug reactions. Functional characterization of the nsSNPs in P450 genes is important to help us understand the impact of genetic factors on P450-mediated drug metabolism and DDIs. To evaluate the effects of P450 nsSNPs on the metabolism and inhibition potential of a candidate drug, tanshinol borneol ester (DBZ), we obtained and experimentally validated eight yeast-expressed human P450 isoforms and their nsSNP variants and tested DBZ using these recombinant P450 enzymes. The results suggested that CYP2C8 is the major enzyme responsible for DBZ metabolism. In addition, compared with prototypic CYP2C8, the allelic variant, CYP2C8.3, produced a 54% decrease in the intrinsic clearance of DBZ. The inhibitory potency of DBZ toward CYP3A4 was greater than that toward other P450 isoforms, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Moreover, the inhibitory potency toward three CYP3A4 allelic variants, CYP3A4.2, CYP3A4.12, and CYP3A4.16, was reduced 2- to 10-fold relative to prototype CYP3A4. These results provide useful information for understanding the influence of P450 genetic polymorphisms on DBZ metabolism and may help to design future clinical trials of DBZ. Our results suggest applications for in vitro P450 assays both for basic research in pharmacogenomics and for drug development.
    Drug metabolism and disposition: the biological fate of chemicals 12/2010; 38(12):2259-65. DOI:10.1124/dmd.110.034439 · 3.25 Impact Factor
  • Yiwen Gao · Duan Liu · Huijuan Wang · Juanli Zhu · Chao Chen ·
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    ABSTRACT: 1. To analyze the polymorphic activities of CYP2C8 and evaluate their impact on drug inhibitory potential, three CYP2C8 allelic variants (CYP2C8.2, CYP2C8.3, and CYP2C8.4), two non-synonymous single nucleotide polymorphic variants (R139K and K399R, carried by CYP2C8.3), and wild-type CYP2C8 (CYP2C8.1) were heterologously expressed in yeast, and their enzymatic activities were characterized. CYP2C8 inhibition-based in vitro and in vivo drug-drug interactions (DDIs) in wild-type and variant CYP2C8s were then predicted. 2. Functional characterization of five CYP2C8 variants revealed similar enzymatic activity in R139K and low activity in CYP2C8.2, CYP2C8.3, CYP2C8.4, and K399R compared with CYP2C8.1. The systematic analysis of these CYP2C8 variants can provide more homogeneous data for predicting CYP2C8 phenotypes and could be applied to personalized drug therapy. 3. Prediction of DDIs indicated that CYP2C8.4, R139K, and K399R dramatically alter the IC(50) values of nifedipine, troglitazone, and raloxifene, and R139K qualitatively and quantitatively reduces the risk of in vivo paclitaxel-raloxifene and paclitaxel-troglitazone interactions. The results provide the first evidence that CYP2C8 inhibition-based DDIs may be influenced by CYP2C8 genetic polymorphisms. These inhibition data can be used by pharmacologists in the design of in vivo studies to further assess and address the potential role of CYP2C8 genotype-dependent inhibition in clinical DDIs.
    Xenobiotica 07/2010; 40(7):467-75. DOI:10.3109/00498254.2010.487163 · 2.20 Impact Factor
  • Huijuan Wang · Yiwen Gao · Pingping MA · Juanli Zhu · Chao Chen ·
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    ABSTRACT: Abstract Aim: Construct a Saccharomyces cerevisiae expressing system and develop an enzymatic detection method for human CYP2C19 polymorphic genes. Methods: The prototype cDNA of CYP 2C19 was obtained by RT-PCR from human liver tissue and cloned into pYES2/CT vector for galactose-inducible expression in yeast. The cloned cDNA was subsequently used as a template to introduce polymorphisms by site-directed mutagenesis and were cloned into the same vector. Transformed yeasts produced large quantities of microsome-bound 2C19 enzymes as determined by Western analysis. The isolated microsomes were used to measure the kinetic constants of 2C19 enzymes in real-time assays using a fluorogenic substrate CEC (3cynao -7-ethoxycoumarin). The inhibition of CYP 2C19 prototype enzyme by known inhibitor drug (tranylcypromine) was tested by serial titration of drugs in the fluorogenic assays. Results: Five cDNA of CYP2C19 corresponding to 2C19*1A (prototype) and variant alleles of 2C19*1B (991A>G, I331V), 2C19*6 (395G>A, R132Q), 2C19*9 (431G>A, R144H), and 2C19*13 (1228C>T, R410C) have been constructed for expression in yeast. The results showed that all enzymes possess robust activity with the exception of 2C19*6; 2C19*6 enzyme failed to show activity even at the highest enzyme concentration tested (3 mg/ml). The Km value of 4 catalytically active enzymes showed little difference , which were all close to 20mol/L; The Vmax value of 2C19*1B and 2C19*13 enzymes were very similar to 2C19*1A, but the Vmax value of 2C19*9 enzyme was 10-fold lower than that of 2C19*1A. Then the inhibition testing of 2C19*1A enzyme testified that tranylcypromine had specific inhibition on CYP2C19. Conclusion: The prototypical and 4 variant forms of human cytochrome P450 2C19 have been expressed in functional form in yeast. The recombinant enzymes show robust activity in real-time fluorogenic assays, and the enzyme activity was specifically inhibited by a known inhibitor of 2C19 enzyme. This work demonstrates the feasibility of large-scale analysis of CYP2C19 polymorphic enzymes in drug mtebabolism and drug-drug interaction study. Key Words : CYP2C19; polymorphism; enzyme kinetics; inhibition testing
    11th European Regional International society for the study of xenobiotics Meeting;