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Prof. Su-Jun Lee
Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Inje University, Busan, South Korea

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0 Functional Genomics
0 Personalized Medicine
0 Pharmacogenomics
0 genetic polymorphisms
0 adverse drug reaction

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Cytochrome P450s

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Review
Published: 14 June 2021 in Journal of Personalized Medicine
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UDP-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that metabolize endogenous fatty acids such as arachidonic acid metabolites, as well as many prescription drugs, such as opioids, antiepileptics, and antiviral drugs. The UGT1A and 2B genes are highly polymorphic, and their genetic variants may affect the pharmacokinetics and hence the responses of many drugs and fatty acids. This study collected data and updated the current view of the molecular functionality of genetic variants on UGT genes that impact drug responses and the susceptibility to human diseases. The functional information of UGT genetic variants with clinical associations are essential to understand the inter-individual variation in drug responses and susceptibility to toxicity.

ACS Style

Yazun Jarrar; Su-Jun Lee. The Functionality of UDP-Glucuronosyltransferase Genetic Variants and their Association with Drug Responses and Human Diseases. Journal of Personalized Medicine 2021, 11, 554 .

AMA Style

Yazun Jarrar, Su-Jun Lee. The Functionality of UDP-Glucuronosyltransferase Genetic Variants and their Association with Drug Responses and Human Diseases. Journal of Personalized Medicine. 2021; 11 (6):554.

Chicago/Turabian Style

Yazun Jarrar; Su-Jun Lee. 2021. "The Functionality of UDP-Glucuronosyltransferase Genetic Variants and their Association with Drug Responses and Human Diseases." Journal of Personalized Medicine 11, no. 6: 554.

Journal article
Published: 22 April 2021 in Journal of Personalized Medicine
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Total serum immunoglobulin E (IgE) is elevated in multiple allergic diseases and is considered a good predictor of atopy. Several studies have been performed on the association of IgE levels with the polymorphism of the ADAM33 gene in asthmatic patients. The aim of this study was to determine whether there is an association between IgE levels and the genetic polymorphisms of the ADAM33 gene (T1, T2, T + 1, V4, S1, S2, and Q-1) in both healthy and asthmatic patients among Jordanians. The clinical data were collected for this case–control study from 267 asthmatic patients and 225 control subjects. Seven genetic polymorphisms (T1, T2, T + 1, V4, S1, S2, and Q-1) of the gene ADAM33 were analyzed using the polymerase chain reaction/restriction fragment length polymorphism method. The minor alleles (G) of T1, (A) of T2, T + 1, and (G) of V4 polymorphisms were associated with a significant increase in total serum IgE levels in adults but not children. The V4 genetic polymorphism, however, showed a significant association with IgE levels in both adults and children. The S1 polymorphism was significantly associated with the codominant module only in the adults. The S2 polymorphism showed a significant association (p-value < 0.05) in both codominant and recessive models. However, in the dominant model for both pediatric control and asthmatic patients, the association between the IgE and S2 polymorphism was insignificant (p-value = 0.7271 and 0.5259, respectively). This study found a statistically significant association between multiple ADAM33 genetic polymorphisms and IgE levels. Such findings add to the growing evidence that the ADAM33 gene has a major impact on IgE levels among asthmatic patients of Jordanian origin.

ACS Style

Malek Zihlif; Amer Imraish; Baeth Al-Rawashdeh; Aya Qteish; Raihan Husami; Rawand Husami; Farah Tahboub; Yazun Jarrar; Su-Jun Lee. The Association of IgE Levels with ADAM33 Genetic Polymorphisms among Asthmatic Patients. Journal of Personalized Medicine 2021, 11, 329 .

AMA Style

Malek Zihlif, Amer Imraish, Baeth Al-Rawashdeh, Aya Qteish, Raihan Husami, Rawand Husami, Farah Tahboub, Yazun Jarrar, Su-Jun Lee. The Association of IgE Levels with ADAM33 Genetic Polymorphisms among Asthmatic Patients. Journal of Personalized Medicine. 2021; 11 (5):329.

Chicago/Turabian Style

Malek Zihlif; Amer Imraish; Baeth Al-Rawashdeh; Aya Qteish; Raihan Husami; Rawand Husami; Farah Tahboub; Yazun Jarrar; Su-Jun Lee. 2021. "The Association of IgE Levels with ADAM33 Genetic Polymorphisms among Asthmatic Patients." Journal of Personalized Medicine 11, no. 5: 329.

Short communication
Published: 24 March 2021 in Biochemical and Biophysical Research Communications
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The glucocorticoid receptor (GR) plays an important role in steroid-dependent regulation of metabolism, development, and the immune response in humans. Although GR is known to be activated by the binding of glucocorticoid, the mechanism of action is poorly understood. We investigated dimerization of GR in the cytoplasm and nuclear trans-localization in response to treatment with the ligand dexamethasone. GFP-tagged GR and FLAG-tagged GR were co-expressed in COS-1 cells, and cell lysates were subjected to co-immunoprecipitation assay with anti-GFP antibody to determine their dimerization. FLAG-GR was co-precipitated with GFP-GR in the cytoplasmic fraction of COS-1 cells. Treatment with the GR agonist dexamethasone significantly decreased the cytoplasmic interaction between FLAG- and GFP-GR, and significantly increased interaction of the GRs in the nuclear fraction. The two amino acids, Pro625 and Ile628 known to be located in GR-GR dimer interface, were mutated to alanine and the influence of the mutation on dimerization, ligand-dependent nuclear localization, and transcriptional activities were determined. Mutant GR showed a dramatic decrease in interaction in the cytoplasmic fraction and no detectable nuclear translocation in the presence or absence of dexamethasone. Furthermore, luciferase assays showed that mutant GR showed no detectable transcriptional activation via the GR-responsive DNA element (GRE) compared to the wild-type. Our results suggest that GR exists as a dimer in the cytoplasm and this dimerization may be essential for GRE-mediated transcriptional activation following ligand binding.

ACS Style

Su-Jun Lee; Ryota Shizu; Masahiko Negishi. Glucocorticoid receptor dimerization in the cytoplasm might be essential for nuclear localization. Biochemical and Biophysical Research Communications 2021, 553, 154 -159.

AMA Style

Su-Jun Lee, Ryota Shizu, Masahiko Negishi. Glucocorticoid receptor dimerization in the cytoplasm might be essential for nuclear localization. Biochemical and Biophysical Research Communications. 2021; 553 ():154-159.

Chicago/Turabian Style

Su-Jun Lee; Ryota Shizu; Masahiko Negishi. 2021. "Glucocorticoid receptor dimerization in the cytoplasm might be essential for nuclear localization." Biochemical and Biophysical Research Communications 553, no. : 154-159.

Review
Published: 11 March 2021 in Journal of Personalized Medicine
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Estrogen sulfotransferase (SULT1E1) is a phase II enzyme that sulfates estrogens to inactivate them and regulate their homeostasis. This enzyme is also involved in the sulfation of thyroid hormones and several marketed medicines. Though the profound action of SULT1E1 in molecular/pathological biology has been extensively studied, its genetic variants and functional studies have been comparatively rarely studied. Genetic variants of this gene are associated with some diseases, especially sex-hormone-related cancers. Comprehending the role and polymorphisms of SULT1E1 is crucial to developing and integrating its clinical relevance; therefore, this study gathered and reviewed various literature studies to outline several aspects of the function, molecular regulation, and polymorphisms of SULT1E1.

ACS Style

Myeongjin Yi; Masahiko Negishi; Su-Jun Lee. Estrogen Sulfotransferase (SULT1E1): Its Molecular Regulation, Polymorphisms, and Clinical Perspectives. Journal of Personalized Medicine 2021, 11, 194 .

AMA Style

Myeongjin Yi, Masahiko Negishi, Su-Jun Lee. Estrogen Sulfotransferase (SULT1E1): Its Molecular Regulation, Polymorphisms, and Clinical Perspectives. Journal of Personalized Medicine. 2021; 11 (3):194.

Chicago/Turabian Style

Myeongjin Yi; Masahiko Negishi; Su-Jun Lee. 2021. "Estrogen Sulfotransferase (SULT1E1): Its Molecular Regulation, Polymorphisms, and Clinical Perspectives." Journal of Personalized Medicine 11, no. 3: 194.

Review
Published: 20 January 2021 in Toxics
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Particulate matter (PM) is a major and the most harmful component of urban air pollution, which may adversely affect human health. PM exposure has been associated with several human diseases, notably respiratory and cardiovascular diseases. In particular, recent evidence suggests that exposure to biomass-derived PM associates with airway inflammation and can aggravate asthma and other allergic diseases. Defective or excess responsiveness in the immune system regulates distinct pathologies, such as infections, hypersensitivity, and malignancies. Therefore, PM-induced modulation of the immune system is crucial for understanding how it causes these diseases and highlighting key molecular mechanisms that can mitigate the underlying pathologies. Emerging evidence has revealed that immune responses to biomass-derived PM exposure are closely associated with the risk of diverse hypersensitivity disorders, including asthma, allergic rhinitis, atopic dermatitis, and allergen sensitization. Moreover, immunological alteration by PM accounts for increased susceptibility to infectious diseases, such as tuberculosis and coronavirus disease-2019 (COVID-19). Evidence-based understanding of the immunological effects of PM and the molecular machinery would provide novel insights into clinical interventions or prevention against acute and chronic environmental disorders induced by biomass-derived PM.

ACS Style

Arulkumar Nagappan; Su Park; Su-Jun Lee; Yuseok Moon. Mechanistic Implications of Biomass-Derived Particulate Matter for Immunity and Immune Disorders. Toxics 2021, 9, 18 .

AMA Style

Arulkumar Nagappan, Su Park, Su-Jun Lee, Yuseok Moon. Mechanistic Implications of Biomass-Derived Particulate Matter for Immunity and Immune Disorders. Toxics. 2021; 9 (2):18.

Chicago/Turabian Style

Arulkumar Nagappan; Su Park; Su-Jun Lee; Yuseok Moon. 2021. "Mechanistic Implications of Biomass-Derived Particulate Matter for Immunity and Immune Disorders." Toxics 9, no. 2: 18.

Original article
Published: 12 May 2020 in Annals of Human Genetics
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The objectives of the present study were to identify CYP4V2 genetic variants and characterize their functional consequences. A total of 26CYP4V2 genetic variants were identified, including seven novel variants in 60 randomly selected healthy subjects. Six protein‐coding variants were studied, including three novel variants (L22V, R287T, and G410C) and three previously reported variants (R36S, Q259K, and H331P). The cDNA sequences encoding each amino acid variant and the wild‐type CYP4V2 protein were cloned into the pcDNA/PDEST40 expression vector and transfected into eukaryotic 293T cells for overexpression of the CYP4V2 coding variants. CYP4V2 H331P and CYP4V2 G410C exhibited significant decreases in activity for lauric acid oxidation (20–30% of wild‐type activity), when compared to the wildtype, which was correlated with low expression of CYP4V2 H331P and G410C substituted proteins. The other four CYP4V2 amino variants were comparable to wild‐type CYP4V2 for lauric acid metabolism. The CYP4V2 H331P and G410C substitutions were predicted to cause a structural change through in silico analysis. In conclusion, the present study provides functional information about CYP4V2 genetic variants. These findings will be valuable for interpreting individual variations in phenotypes associated with CYP4V2 function in the clinical setting.

ACS Style

Yazun Bashir Jarrar; Jae‐Gook Shin; Su-Jun Lee. Identification and functional characterization of CYP4V2 genetic variants exhibiting decreased activity of lauric acid metabolism. Annals of Human Genetics 2020, 84, 400 -411.

AMA Style

Yazun Bashir Jarrar, Jae‐Gook Shin, Su-Jun Lee. Identification and functional characterization of CYP4V2 genetic variants exhibiting decreased activity of lauric acid metabolism. Annals of Human Genetics. 2020; 84 (5):400-411.

Chicago/Turabian Style

Yazun Bashir Jarrar; Jae‐Gook Shin; Su-Jun Lee. 2020. "Identification and functional characterization of CYP4V2 genetic variants exhibiting decreased activity of lauric acid metabolism." Annals of Human Genetics 84, no. 5: 400-411.

Journal article
Published: 17 January 2020 in Prostaglandins, Leukotrienes and Essential Fatty Acids
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20-hydroxyeicosatetraenoic acid (20-HETE) is an arachidonic acid metabolite which is known to increase platelet aggregation and cardiovascular risk. In this study, nine non-steroidal anti-inflammatory drugs (NSAIDs) selected by chemical structures were screened to determine their effects on the glucuronidation of 20-HETE using human liver microsomes (HLMs). Then, the combined effects of the selected NSAID and genetic polymorphisms in UDP-glucuronosyltransferase (UGT) were investigated. Among the tested NSAIDs, diclofenac was the strongest inhibitor of 20-HETE glucuronidation with an IC50 value of 3.5 μM. Celecoxib, naproxen, mefenamic acid, ibuprofen, and indomethacin showed modest inhibition with IC50 values of 77, 91, 190, 208, and 220 μM, respectively, while acetylsalicylic acid, rofecoxib, and meloxicam did not inhibit 20-HETE glucuronidation. Glucuronidation of 20-HETE by UGT2B7 and UGT1A9 recombinant enzymes was significantly inhibited by indomethacin, mefanemic acid, diclofenac, ibuprofen, naproxen, and celecoxib (P < 0.001). In addition, diclofenac exhibited a competitive inhibition mechanism with the Km value of 20-HETE glucuronidation increasing from 23.5 μM to 62 μM in the presence of 3.5 μM diclofenac. Diclofenac further decreased 20-HETE glucuronidation in HLMs carrying UGT2B7*2 alleles compared with the wild-type HLMs. The results from this study would be useful in understanding the alteration of 20-HETE levels in relation to NSAID and UGT genetic polymorphisms.

ACS Style

Yazun Bashir Jarrar; Dong Hyun Kim; Su-Jun Lee; Jae-Gook Shin. Inhibition of 20-hydroxyeicosatetraenoic acid (20-HETE) glucuronidation by non-steroidal anti-inflammatory drugs in human liver microsomes and recombinant UDP-glucuronosyltransferase enzymes. Prostaglandins, Leukotrienes and Essential Fatty Acids 2020, 153, 102055 .

AMA Style

Yazun Bashir Jarrar, Dong Hyun Kim, Su-Jun Lee, Jae-Gook Shin. Inhibition of 20-hydroxyeicosatetraenoic acid (20-HETE) glucuronidation by non-steroidal anti-inflammatory drugs in human liver microsomes and recombinant UDP-glucuronosyltransferase enzymes. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2020; 153 ():102055.

Chicago/Turabian Style

Yazun Bashir Jarrar; Dong Hyun Kim; Su-Jun Lee; Jae-Gook Shin. 2020. "Inhibition of 20-hydroxyeicosatetraenoic acid (20-HETE) glucuronidation by non-steroidal anti-inflammatory drugs in human liver microsomes and recombinant UDP-glucuronosyltransferase enzymes." Prostaglandins, Leukotrienes and Essential Fatty Acids 153, no. : 102055.

Review
Published: 31 August 2019 in International Journal of Molecular Sciences
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Enzymes in the cytochrome P450 4 (CYP4) family are involved in the metabolism of fatty acids, xenobiotics, therapeutic drugs, and signaling molecules, including eicosanoids, leukotrienes, and prostanoids. As CYP4 enzymes play a role in the maintenance of fatty acids and fatty-acid-derived bioactive molecules within a normal range, they have been implicated in various biological functions, including inflammation, skin barrier, eye function, cardiovascular health, and cancer. Numerous studies have indicated that genetic variants of CYP4 genes cause inter-individual variations in metabolism and disease susceptibility. Genetic variants of CYP4A11, 4F2 genes are associated with cardiovascular diseases. Mutations of CYP4B1, CYP4Z1, and other CYP4 genes that generate 20-HETE are a potential risk for cancer. CYP4V2 gene variants are associated with ocular disease, while those of CYP4F22 are linked to skin disease and CYP4F3B is associated with the inflammatory response. The present study comprehensively collected research to provide an updated view of the molecular functionality of CYP4 genes and their associations with human diseases. Functional analysis of CYP4 genes with clinical implications is necessary to understand inter-individual variations in disease susceptibility and for the development of alternative treatment strategies.

ACS Style

Yazun Bashir Jarrar; Su-Jun Lee. Molecular Functionality of Cytochrome P450 4 (CYP4) Genetic Polymorphisms and Their Clinical Implications. International Journal of Molecular Sciences 2019, 20, 4274 .

AMA Style

Yazun Bashir Jarrar, Su-Jun Lee. Molecular Functionality of Cytochrome P450 4 (CYP4) Genetic Polymorphisms and Their Clinical Implications. International Journal of Molecular Sciences. 2019; 20 (17):4274.

Chicago/Turabian Style

Yazun Bashir Jarrar; Su-Jun Lee. 2019. "Molecular Functionality of Cytochrome P450 4 (CYP4) Genetic Polymorphisms and Their Clinical Implications." International Journal of Molecular Sciences 20, no. 17: 4274.

Journal article
Published: 01 April 2019 in Drug Metabolism and Pharmacokinetics
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The objective of the present study was to investigate the effects of cytochrome b5 (cytb5) on the drug metabolism catalyzed by CYP2C9, CYP2C19 and CYP3A4. Activities of CYP2C9, CYP2C19, and CYP3A4 were determined by using the prototypical substrates tolbutamide, omeprazole and midazolam, respectively. Cytb5 protein and mRNA contents showed large inter-individual variations with 11- and 6-fold range, respectively. All of three P450s showed an increased activity in proportion to the amount of cytb5 expression. Particularly, CYP3A4 showed the strongest correlation between cytb5 protein amount and the activity, followed by CYP2C9 and CYP2C19. The putative splicing variant, c.288G>A (rs7238987) was identified and was screened in 36 liver tissues by direct DNA sequencing. Liver tissues having a splicing variant exhibited unexpected sizes of cytb5 mRNA and a decreased expression tendency of cytb5 protein compared to the wild-type. A decreased activity in the metabolism of the CYP2C19 substrate omeprazole was observed in liver tissues carrying the splicing variant when compared to the wild-type Cytb5 (P<0.05). The present results propose that different expression of cytb5 can cause variations in CYP mediated drug metabolism, which may explain, at least in part, the inter-individual difference in drug responses in addition to the CYP genetic polymorphisms.

ACS Style

Sung-Eun Yoo; Myeongjin Yi; Woo-Young Kim; Sun-Ah Cho; Sang Seop Lee; Su-Jun Lee; Jae-Gook Shin. Influences of cytochrome b5 expression and its genetic variant on the activity of CYP2C9, CYP2C19 and CYP3A4. Drug Metabolism and Pharmacokinetics 2019, 34, 201 -208.

AMA Style

Sung-Eun Yoo, Myeongjin Yi, Woo-Young Kim, Sun-Ah Cho, Sang Seop Lee, Su-Jun Lee, Jae-Gook Shin. Influences of cytochrome b5 expression and its genetic variant on the activity of CYP2C9, CYP2C19 and CYP3A4. Drug Metabolism and Pharmacokinetics. 2019; 34 (3):201-208.

Chicago/Turabian Style

Sung-Eun Yoo; Myeongjin Yi; Woo-Young Kim; Sun-Ah Cho; Sang Seop Lee; Su-Jun Lee; Jae-Gook Shin. 2019. "Influences of cytochrome b5 expression and its genetic variant on the activity of CYP2C9, CYP2C19 and CYP3A4." Drug Metabolism and Pharmacokinetics 34, no. 3: 201-208.

Journal article
Published: 01 September 2017 in Toxicology and Applied Pharmacology
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Because macrophages respond to a variety of pathological and pharmacological reagents, understanding the role of P450s in macrophages is important for therapeutic intervention. There has been a lack of research on CYP4 in macrophages, but fatty acid accumulation and lipid trafficking in macrophages have been suggested to be a main cause of atherosclerosis. All human CYP4 genes (n=12) were screened in THP1 macrophages by gene-specific reverse transcriptase-polymerase chain reaction (RT-PCR). Only CYP4V2 exhibited strong expression of both mRNA and protein. Expression levels of both CYP4V2 mRNA and protein were significantly reduced after treatment with peroxisome proliferator-activated receptor gamma (PPARγ) antagonist GW9662. However, the expression levels of CYP4V2 were not changed by PPARα antagonist (GW6471) and liver X receptor alpha antagonist (22-S hydroxycholesterol). A metabolite of the CYP4V2 enzyme, 12-hydroxydodecanoic acid, was detected in THP1 macrophages, and this metabolite was significantly decreased after treatment with the PPARγ inhibitor GW9662 (>80% decreased, p<0.05). In summary, fatty acid metabolizing protein CYP4V2 was identified in human THP1 macrophages, and its expression was regulated by PPARγ. Further study is required to understand the role of CYP4V2 with regard to fat accumulation in the activated macrophage and atherosclerotic plaque development.

ACS Style

Myeongjin Yi; Jae-Gook Shin; Su-Jun Lee. Expression of CYP4V2 in human THP1 macrophages and its transcriptional regulation by peroxisome proliferator-activated receptor gamma. Toxicology and Applied Pharmacology 2017, 330, 100 -106.

AMA Style

Myeongjin Yi, Jae-Gook Shin, Su-Jun Lee. Expression of CYP4V2 in human THP1 macrophages and its transcriptional regulation by peroxisome proliferator-activated receptor gamma. Toxicology and Applied Pharmacology. 2017; 330 ():100-106.

Chicago/Turabian Style

Myeongjin Yi; Jae-Gook Shin; Su-Jun Lee. 2017. "Expression of CYP4V2 in human THP1 macrophages and its transcriptional regulation by peroxisome proliferator-activated receptor gamma." Toxicology and Applied Pharmacology 330, no. : 100-106.

Journal article
Published: 01 April 2017 in Archives of Biochemistry and Biophysics
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CYP4F11, together with CYP4F2, plays an important role in the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid. We identified 21 variants by whole exome sequencing, including 4 non-synonymous variants in Korean subjects. The proteins of the wild-type CYP4F11 and the four coding variants (C276R, D315N, D374Y, and D446N) were expressed in Escherichia coli DH5α cells and purified to give cytochrome P450-specific carbon monoxide difference spectra. Wild-type CYP4F2 was also expressed and purified to compare its activity with the CYP4F11 wild-type. Wild-type CYP4F11 exhibited the highest maximal clearance for erythromycin N-demethylase activity followed by the variants D374Y, D446N, C276R, and D315N. In particular, the CYP4F11 D315N protein showed about 50% decrease in intrinsic clearance compared to the wild type. The ability of wild-type CYP4F11 and the variants to synthesize 20-HETE from arachidonic acid was similar; the CYP4F11 D315N variant, however, showed only 68% of wild-type activity. Furthermore, the ability of CYP4F2 to synthesize 20-HETE was 1.7-fold greater than that of CYP4F11. Overall, our results suggest that the metabolism of CYP4F11 substrates may be reduced in individuals carrying the CYP4F11 D315N genetic variant and individuals carrying the common D446N CYP4F11 variant likely exhibit comparable 20-HETE synthesis as individuals expressing wild-type CYP4F11.

ACS Style

Myeongjin Yi; Sun-Ah Cho; Jungki Min; Dong Hyun Kim; Jae-Gook Shin; Su-Jun Lee. Functional characterization of a common CYP4F11 genetic variant and identification of functionally defective CYP4F11 variants in erythromycin metabolism and 20-HETE synthesis. Archives of Biochemistry and Biophysics 2017, 620, 43 -51.

AMA Style

Myeongjin Yi, Sun-Ah Cho, Jungki Min, Dong Hyun Kim, Jae-Gook Shin, Su-Jun Lee. Functional characterization of a common CYP4F11 genetic variant and identification of functionally defective CYP4F11 variants in erythromycin metabolism and 20-HETE synthesis. Archives of Biochemistry and Biophysics. 2017; 620 ():43-51.

Chicago/Turabian Style

Myeongjin Yi; Sun-Ah Cho; Jungki Min; Dong Hyun Kim; Jae-Gook Shin; Su-Jun Lee. 2017. "Functional characterization of a common CYP4F11 genetic variant and identification of functionally defective CYP4F11 variants in erythromycin metabolism and 20-HETE synthesis." Archives of Biochemistry and Biophysics 620, no. : 43-51.

Case reports
Published: 01 June 2016 in Journal of Clinical Research in Pediatric Endocrinology
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The CYP19A1 gene product aromatase is responsible for estrogen synthesis and androgen/estrogen equilibrium in many tissues, particularly in the placenta and gonads. Aromatase deficiency can cause various clinical phenotypes resulting from excessive androgen accumulation and insufficient estrogen synthesis during the pre- and postnatal periods. In this study, our aim was to determine the clinical characteristics and CYP19A1 mutations in three patients from a large Turkish pedigree. The cases were the newborns referred to our clinic for clitoromegaly and labial fusion. Virilizing signs such as severe acne formation, voice deepening, and clitoromegaly were noted in the mothers during pregnancy. Preliminary diagnosis was aromatase deficiency. Therefore, direct DNA sequencing of CYP19A1 was performed in samples from parents (n=5) and patients (n=3). In all patients, a novel homozygous insertion mutation in the fifth exon (568insC) was found to cause a frameshift in the open reading frame and to truncate the protein prior to the heme-binding region which is crucial for enzymatic activity. The parents were found to be heterozygous for this mutation. Additionally, all patients had hypoplastic ovaries instead of cystic and enlarged ovaries. A novel 568C insertion mutation in CYP19A1 can lead to severe aromatase deficiency. Homozygosity for this mutation is associated with the development of hypoplastic ovaries. This finding provides an important genetic marker for understanding the physiological function of aromatase in fetal ovarian development.

ACS Style

Sema Akçurin; Doğa Türkkahraman; Woo-Young Kim; Erdem Durmaz; Jae-Gook Shin; Su-Jun Lee. A Novel Null Mutation in P450 Aromatase Gene (CYP19A1) Associated with Development of Hypoplastic Ovaries in Humans. Journal of Clinical Research in Pediatric Endocrinology 2016, 8, 205 -210.

AMA Style

Sema Akçurin, Doğa Türkkahraman, Woo-Young Kim, Erdem Durmaz, Jae-Gook Shin, Su-Jun Lee. A Novel Null Mutation in P450 Aromatase Gene (CYP19A1) Associated with Development of Hypoplastic Ovaries in Humans. Journal of Clinical Research in Pediatric Endocrinology. 2016; 8 (2):205-210.

Chicago/Turabian Style

Sema Akçurin; Doğa Türkkahraman; Woo-Young Kim; Erdem Durmaz; Jae-Gook Shin; Su-Jun Lee. 2016. "A Novel Null Mutation in P450 Aromatase Gene (CYP19A1) Associated with Development of Hypoplastic Ovaries in Humans." Journal of Clinical Research in Pediatric Endocrinology 8, no. 2: 205-210.

Journal article
Published: 01 March 2015 in Archives of Biochemistry and Biophysics
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Prostacyclin synthase (CYP8A1) is an enzyme responsible for the biosynthesis of prostacyclin (PGI2) which inhibits platelet activation and exhibits anti-inflammatory effect. The objectives of this study were to identify CYP8A1 genetic variants and characterize functional consequences of CYP8A1 variants. In total, 27 variants including four previously unidentified single-nucleotide polymorphisms (SNPs) were identified by direct DNA sequencing in Koreans (n=48). Among them, CYP8A1 A447T and E314Stop were newly assigned as CYP8A1(∗)5 and CYP8A1(∗)6 by the Human Cytochrome P450 Allele Nomenclature Committee, respectively. CYP8A1(∗)5 was found in the heme binding area in three individuals as a heterozygous mutation. To investigate the functional change of CYP8A1(∗)5, CYP8A1(∗)5 and wild-type CYP8A1 protein were overexpressed in an Escherichia coli expression system and purified. Metabolism of PGH2 by the CYP8A1(∗)5 protein exhibited significantly decreased activity, resulting in a 45% decrease in Vmax and a 1.8-fold decrease in intrinsic clearance compared to the wild-type. Based on the predicted crystal structure of CYP8A1(∗)5 using the Molecular Operating Environment platform, the distance from CYP8A1 Cys441 to the heme was altered with a significantly changed binding free energy for the mutant protein. Further studies would be needed to determine the effect of CYP8A1(∗)5 on PGI2 levels in humans.

ACS Style

Sun-Ah Cho; Katie Jo Rohn-Glowacki; Yazun B. Jarrar; Myeongjin Yi; Woo-Young Kim; Jae-Gook Shin; Su-Jun Lee. Analysis of genetic polymorphism and biochemical characterization of a functionally decreased variant in prostacyclin synthase gene (CYP8A1) in humans. Archives of Biochemistry and Biophysics 2015, 569, 10 -18.

AMA Style

Sun-Ah Cho, Katie Jo Rohn-Glowacki, Yazun B. Jarrar, Myeongjin Yi, Woo-Young Kim, Jae-Gook Shin, Su-Jun Lee. Analysis of genetic polymorphism and biochemical characterization of a functionally decreased variant in prostacyclin synthase gene (CYP8A1) in humans. Archives of Biochemistry and Biophysics. 2015; 569 ():10-18.

Chicago/Turabian Style

Sun-Ah Cho; Katie Jo Rohn-Glowacki; Yazun B. Jarrar; Myeongjin Yi; Woo-Young Kim; Jae-Gook Shin; Su-Jun Lee. 2015. "Analysis of genetic polymorphism and biochemical characterization of a functionally decreased variant in prostacyclin synthase gene (CYP8A1) in humans." Archives of Biochemistry and Biophysics 569, no. : 10-18.

Journal article
Published: 01 November 2014 in Journal of Lipid Research
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The compound 20-HETE is involved in numerous physiological functions, including blood pressure and platelet aggregation. Glucuronidation of 20-HETE by UDP-glucuronosyltransferases (UGTs) is thought to be a primary pathway of 20-HETE elimination in humans. The present study identified major UGT enzymes responsible for 20-HETE glucuronidation and investigated their genetic influence on the glucuronidation reaction using human livers (n = 44). Twelve recombinant UGTs were screened to identify major contributors to 20-HETE glucuronidation. Based on these results, UGT2B7, UGT1A9, and UGT1A3 exhibited as major contributors to 20-HETE glucuronidation. The Km values of 20-HETE glucuronidation by UGT1A3, UGT1A9, and UGT2B7 were 78.4, 22.2, and 14.8 μM, respectively, while Vmax values were 1.33, 1.78, and 1.62 nmol/min/mg protein, respectively. Protein expression levels and genetic variants of UGT1A3, UGT1A9, and UGT2B7 were analyzed in human livers using Western blotting and genotyping, respectively. Glucuronidation of 20-HETE was significantly correlated with the protein levels of UGT2B7 (r2 = 0.33, P < 0.001) and UGT1A9 (r2 = 0.31, P < 0.001), but not UGT1A3 (r2 = 0.02, P > 0.05). A correlation between genotype and 20-HETE glucuronidation revealed that UGT2B7 802C>T, UGT1A9 −118T9>T10, and UGT1A9 1399T>C significantly altered 20-HETE glucuronide formation (P < 0.05–0.001). Increased levels of 20-HETE comprise a risk factor for cardiovascular diseases, and the present data may increase our understanding of 20-HETE metabolism and cardiovascular complications.

ACS Style

Yazun Jarrar; Eun-Young Cha; Kyung-Ah Seo; Jong-Lyul Ghim; Hyo-Ji Kim; Dong Hyun Kim; Su-Jun Lee; Jae-Gook Shin. Determination of major UDP-glucuronosyltransferase enzymes and their genotypes responsible for 20-HETE glucuronidation. Journal of Lipid Research 2014, 55, 2334 -2342.

AMA Style

Yazun Jarrar, Eun-Young Cha, Kyung-Ah Seo, Jong-Lyul Ghim, Hyo-Ji Kim, Dong Hyun Kim, Su-Jun Lee, Jae-Gook Shin. Determination of major UDP-glucuronosyltransferase enzymes and their genotypes responsible for 20-HETE glucuronidation. Journal of Lipid Research. 2014; 55 (11):2334-2342.

Chicago/Turabian Style

Yazun Jarrar; Eun-Young Cha; Kyung-Ah Seo; Jong-Lyul Ghim; Hyo-Ji Kim; Dong Hyun Kim; Su-Jun Lee; Jae-Gook Shin. 2014. "Determination of major UDP-glucuronosyltransferase enzymes and their genotypes responsible for 20-HETE glucuronidation." Journal of Lipid Research 55, no. 11: 2334-2342.

Journal article
Published: 05 May 2014 in International Journal of Molecular Sciences
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There has been a wide range of inter-individual variations in platelet responses to clopidogrel. The variations in response to clopidogrel can be driven by genetic polymorphisms involved in the pathway of absorption, distribution, metabolism, excretion, and the target receptor P2Y12. A set of genetic variants known for causing variations in clopidogrel responses was selected, which included CYP2C19*2, *3, *17, CYP2B6*4, *6, *9, CYP3A4*18, CYP3A5*3, MDR1 2677G > T/A, 3435C > T, and P2Y12 H2 (742T > C). The simultaneous detection of these 10 variants was developed by using a multiplex PCR and single-base extension (MSSE) methodology. The newly developed genotyping test was confirmed by direct DNA sequencing in the representative positive control samples and validated in an extended set of 100 healthy Korean subjects. Genotyping results from the developed MSSE exhibited a perfect concordance with the direct DNA sequencing data and all of variants tested in 100 healthy Korean subjects were in agreement with Hardy-Weinberg equilibrium (p > 0.05). The present molecular diagnostic studies provide an accurate, convenient, and fast genotyping method for the detection of multiple variants. This would be helpful for researchers, as well as clinicians, to use genetic information toward more personalized medicine of clopidogrel and other antiplatelet drugs in the future.

ACS Style

Hye-Eun Jeong; Su-Jun Lee; Eun-Young Cha; Eun-Young Kim; Ho-Sook Kim; Young Hwan Song; Jae-Gook Shin. Development of a Multiplex and Cost-Effective Genotype Test toward More Personalized Medicine for the Antiplatelet Drug Clopidogrel. International Journal of Molecular Sciences 2014, 15, 7699 -7710.

AMA Style

Hye-Eun Jeong, Su-Jun Lee, Eun-Young Cha, Eun-Young Kim, Ho-Sook Kim, Young Hwan Song, Jae-Gook Shin. Development of a Multiplex and Cost-Effective Genotype Test toward More Personalized Medicine for the Antiplatelet Drug Clopidogrel. International Journal of Molecular Sciences. 2014; 15 (5):7699-7710.

Chicago/Turabian Style

Hye-Eun Jeong; Su-Jun Lee; Eun-Young Cha; Eun-Young Kim; Ho-Sook Kim; Young Hwan Song; Jae-Gook Shin. 2014. "Development of a Multiplex and Cost-Effective Genotype Test toward More Personalized Medicine for the Antiplatelet Drug Clopidogrel." International Journal of Molecular Sciences 15, no. 5: 7699-7710.

Journal article
Published: 01 September 2013 in Prostaglandins, Leukotrienes and Essential Fatty Acids
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Although cytochrome P450s (CYPs) have been identified in most human cells, identification of CYPs in human platelets remains poorly explored. CYP expressions in human platelets were screened by using reverse transcriptase-polymerase chain reaction and western blot analysis followed by functional assays using arachidonic acid (ARA). CYP1A1, 2U1, 2J2, 4A11, 4F2, and 5A1 were expressed as both proteins and mRNAs in platelets. Ethoxyresorufin-O-deethylase activity was observed in platelets and this activity was significantly decreased after treatment with the general P450 inhibitor SKF-525A and the CYP1A inhibitor, α-naphthoflavone (40-45%, P<0.001). Seventeen ARA metabolites were detected in ARA-treated platelets. Among these, the levels of 20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids were significantly decreased with the treatment of the P450 ω-hydroxylase inhibitor 17-octadecynoic acid (P<0.05-0.001). In summary, multiple ARA-metabolizing P450s were identified in human platelets. These findings may provide an important resource for understanding physiological function of platelet.

ACS Style

Yazun B. Jarrar; Sun-Ah Cho; Kyung-Suk Oh; Dong-Hyun Kim; Jae-Gook Shin; Su-Jun Lee. Identification of cytochrome P450s involved in the metabolism of arachidonic acid in human platelets. Prostaglandins, Leukotrienes and Essential Fatty Acids 2013, 89, 227 -234.

AMA Style

Yazun B. Jarrar, Sun-Ah Cho, Kyung-Suk Oh, Dong-Hyun Kim, Jae-Gook Shin, Su-Jun Lee. Identification of cytochrome P450s involved in the metabolism of arachidonic acid in human platelets. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2013; 89 (4):227-234.

Chicago/Turabian Style

Yazun B. Jarrar; Sun-Ah Cho; Kyung-Suk Oh; Dong-Hyun Kim; Jae-Gook Shin; Su-Jun Lee. 2013. "Identification of cytochrome P450s involved in the metabolism of arachidonic acid in human platelets." Prostaglandins, Leukotrienes and Essential Fatty Acids 89, no. 4: 227-234.

Article
Published: 31 May 2013 in In Vitro Cellular & Developmental Biology - Animal
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Cytochrome P450s (P450s) are involved in the metabolism of arachidonic acid (ARA), and ARA metabolites are associated with various cellular signaling pathways, such as blood hemostasis and inflammation. The present study demonstrates the expression of ARA-metabolizing P450s in the human megakaryocytic Dami cells using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunublotting analysis followed by activity assays using ARA as a substrate. In addition to the previously identified CYP5A1, both protein and mRNAs of CYP1A1, 2U1, and 2J2 bands were detected. Ethoxyresorufin-O-deethylase (EROD) activity was observed in Dami cells, and its activity was significantly decreased after treatment with the P450 inhibitor SKF-525A when compared to the control groups (60% reduction, P < 0.001). CYP1A1 protein expression in Dami cells was induced by 3-methylenecholantheren. This increase in CYP1A1 protein level was correlated with enhanced EROD activity (fourfold increase vs. the control), as well as with increased metabolites, such as 20-hydroxyeicosatrienoic acid (20-HETE), 14, 15-EET (14-,15-epoxyeicosatrienoic acid), and 14, 15-dihydroxyeicosatrienoic acid (14, 15-DHET). The expression of soluble epoxide hydrolase, an enzyme responsible for the synthesis of DHETs from EETs, was confirmed by RT-PCR. Furthermore, 15 ARA metabolites, including 8,9-EET, 14,15-EET, and 20-HETE, were detected by LC-MS/MS in ARA-treated Dami cells, and their levels were decreased with the treatment of the SKF-525A. The present data suggest the possibility that the P450s play a role in the metabolism of ARA and other CYP-related substrates in human megakaryocytes and that P450 expression in megakaryocytic cell lines may predict their existences in platelets with functional activities.

ACS Style

Yazun Jarrar; Jae-Gook Shin; Su-Jun Lee. Expression of arachidonic acid-metabolizing cytochrome P450s in human megakaryocytic Dami cells. In Vitro Cellular & Developmental Biology - Animal 2013, 49, 492 -500.

AMA Style

Yazun Jarrar, Jae-Gook Shin, Su-Jun Lee. Expression of arachidonic acid-metabolizing cytochrome P450s in human megakaryocytic Dami cells. In Vitro Cellular & Developmental Biology - Animal. 2013; 49 (7):492-500.

Chicago/Turabian Style

Yazun Jarrar; Jae-Gook Shin; Su-Jun Lee. 2013. "Expression of arachidonic acid-metabolizing cytochrome P450s in human megakaryocytic Dami cells." In Vitro Cellular & Developmental Biology - Animal 49, no. 7: 492-500.

Journal article
Published: 01 January 2013 in Frontiers in Genetics
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More than 30 years of genetic research on the CYP2C19 gene alone has identified approximately 2,000 reference single nucleotide polymorphisms (rsSNPs) containing 28 registered alleles in the P450 Allele Nomenclature Committee and the number continues to increase. However, knowledge of CYP2C19 SNPs remains limited with respect to biological functions. Functional information on the variant is essential for justifying its clinical use. Only common variants (minor allele frequency >5%) that represent CYP2C19*2, *3, *17, and others have been mostly studied. Discovery of new genetic variants is outstripping the generation of knowledge on the biological meanings of existing variants. Alternative strategies may be needed to fill this gap. The present study summarizes up-to-date knowledge on functional CYP2C19 variants discovered in phenotyped humans studied at the molecular level in vitro. Understanding the functional meanings of CYP2C19 variants is an essential step toward shifting the current medical paradigm to highly personalized therapeutic regimens.

ACS Style

Su-Jun Lee. Clinical Application of CYP2C19 Pharmacogenetics Toward More Personalized Medicine. Frontiers in Genetics 2013, 3, 318 .

AMA Style

Su-Jun Lee. Clinical Application of CYP2C19 Pharmacogenetics Toward More Personalized Medicine. Frontiers in Genetics. 2013; 3 ():318.

Chicago/Turabian Style

Su-Jun Lee. 2013. "Clinical Application of CYP2C19 Pharmacogenetics Toward More Personalized Medicine." Frontiers in Genetics 3, no. : 318.

Research article
Published: 02 July 2012 in Platelets
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P2Y12 is an important G protein-coupled receptor that is involved in ADP-induced platelet aggregation, which is essential for normal haemostasis. Gender differences in the incidence of cardiovascular disease have been proposed to be linked to the effects of sex hormones on cardiovascular-related genes. We examined the influences of testosterone and 17β-oestradiol on P2Y12 gene expression in megakaryocytic DAMI cell line. Altered levels of P2Y12 mRNA, protein and the cAMP-dependent vasodilator-stimulated phosphoprotein-Ser157 (VASP-Ser157) phosphorylation were investigated after treatment with 17β-oestradioal or testosterone as compared to the control groups. Quantitative real-time PCR revealed that the P2Y12 mRNA levels were increased by testosterone in a dose-dependent manner, whereas 17β-oestrodiol had no effect on P2Y12 gene expression. Induction of the P2Y12 protein by testosterone was found in Western blots of the proteins isolated from testosterone-treated cells. Testosterone-mediated P2Y12 expression was repressed at both the transcriptional and translational levels by the anti-androgen receptor bicalutamide. Treatment with testosterone also resulted in a decrease in the level of VASP-Ser157 phosphorylation, as compared to the control group. The decrease in the level of VASP-Ser157 phosphorylation was reversed by bicalutamide. These findings suggest a novel pathway for testosterone regulation of P2Y12 expression in a megakaryocytic DAMI cell line. Further studies using primary human megakaryocytes and platelets could be necessary to know the effect of hormones on the P2Y12 expression in circulating platelets.

ACS Style

Su-Jun Lee; Jeong-Ah Kwon; Sun-Ah Cho; Yazun Jarrar; Jae-Gook Shin. Effects of testosterone and 17β-oestradiol on expression of the G protein-coupled receptor P2Y12 in megakaryocytic DAMI cells. Platelets 2012, 23, 579 -585.

AMA Style

Su-Jun Lee, Jeong-Ah Kwon, Sun-Ah Cho, Yazun Jarrar, Jae-Gook Shin. Effects of testosterone and 17β-oestradiol on expression of the G protein-coupled receptor P2Y12 in megakaryocytic DAMI cells. Platelets. 2012; 23 (8):579-585.

Chicago/Turabian Style

Su-Jun Lee; Jeong-Ah Kwon; Sun-Ah Cho; Yazun Jarrar; Jae-Gook Shin. 2012. "Effects of testosterone and 17β-oestradiol on expression of the G protein-coupled receptor P2Y12 in megakaryocytic DAMI cells." Platelets 23, no. 8: 579-585.

Comparative study
Published: 01 January 2012 in Drug Metabolism and Pharmacokinetics
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CYP3A4 and CYP3A5 require cytochrome b5 (b5) and NADPH-cytochrome P450 oxidoreductase (CPR) for optimum metabolism, but little is known about the specific requirements for b5 and CPR to produce optimal activities for these enzymes. The metabolism of testosterone (TT) by CYP3A4 and CYP3A5 were analyzed by various combinations of b5 and CPR using a fixed amount of recombinant P450 which had been purified from an E. coli expression system. CYP3A4 and CYP3A5 required 4 and 8-fold more of CPR than of the P450s, respectively, for optimal activity. The requirement of b5 for optimal activity showed the same pattern for both CYP3A4 and CYP3A5, exhibiting a gradual stimulation of the activity reaching a maximum at 16 fold more b5 than P450. Although CYP3A4 exhibited higher activities than the CYP3A5 in all combinations, both enzymes exhibited the same dependency profile for b5 and CPR. Therefore, the stronger activity of CYP3A4 compared to CYP3A5 appears to be intrinsic to the CYP3A4 protein itself and not to different requirements for b5 and CPR. Since the relative amounts of b5 and CPR are important in the maintenance of CYP3A4 and CYP3A5 activities, different levels of these proteins in vitro and invivo may cause altered metabolism of their substrates or misinterpretation of enzyme properties.

ACS Style

Su-Jun Lee; Joyce A. Goldstein. Comparison of CYP3A4 and CYP3A5: The Effects of Cytochrome b5 and NADPH-cytochrome P450 Reductase on Testosterone Hydroxylation Activities. Drug Metabolism and Pharmacokinetics 2012, 27, 663 -667.

AMA Style

Su-Jun Lee, Joyce A. Goldstein. Comparison of CYP3A4 and CYP3A5: The Effects of Cytochrome b5 and NADPH-cytochrome P450 Reductase on Testosterone Hydroxylation Activities. Drug Metabolism and Pharmacokinetics. 2012; 27 (6):663-667.

Chicago/Turabian Style

Su-Jun Lee; Joyce A. Goldstein. 2012. "Comparison of CYP3A4 and CYP3A5: The Effects of Cytochrome b5 and NADPH-cytochrome P450 Reductase on Testosterone Hydroxylation Activities." Drug Metabolism and Pharmacokinetics 27, no. 6: 663-667.