• Animal Bioscience
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• v.34 no.2
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• pp.312-319
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• 2021

Objective: Stress-induced cytotoxicity caused by xenobiotics and endogenous metabolites induces the production of reactive oxygen species and often results in damage to cellular components such as DNA, proteins, and lipids. The cytochrome P450 (CYP) family of enzymes are most abundant in hepatocytes, where they play key roles in regulating cellular stress responses. We aimed to determine the effects of the antioxidant compound, methylsulfonylmethane (MSM), on oxidative stress response, and study the cytochrome P450 family 3 subfamily A (CYP3A) gene expression in fetal horse hepatocytes. Methods: The expression of hepatocyte markers and CYP3A family genes (CYP3A89, CYP3A93, CYP3A94, CYP3A95, CYP3A96, and CYP3A97) were assessed in different organ tissues of the horse and fetal horse liver-derived cells (FHLCs) using quantitative reverse transcription polymerase chain reaction. To elucidate the antioxidant effects of MSM on FHLCs, cell viability, levels of oxidative markers, and gene expression of CYP3A were investigated in H2O2-induced oxidative stress in the presence and absence of MSM. Results: FHLCs exhibited features of liver cells and simultaneously maintained the typical genetic characteristics of normal liver tissue; however, the expression profiles of some liver markers and CYP3A genes, except that of CYP3A93, were different. The expression of CYP3A93 specifically increased after the addition of H2O2 to the culture medium. MSM treatment reduced oxidative stress as well as the expression of CYP3A93 and heme oxygenase 1, an oxidative marker in FHLCs. Conclusion: MSM could reduce oxidative stress and hepatotoxicity in FHLCs by altering CYP3A93 expression and related signaling pathways.

• Biomolecules & Therapeutics
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• v.18 no.2
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• pp.226-232
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• 2010

The aim of this study was to investigate the effect of atrovasatatin on the pharmacokinetics of nicardipine after oral and intravenous administration of nicardipine to rats. Nicardipine was administered orally (12 mg/kg) or intravenously (i.v., 4 mg/kg) without or with oral administration of atrovasatatin (0.3 or 1.0 mg/kg) to rats. The effect of atorvastatin on the P-glycoprotein (P-gp) as well as CYP3A4 activity was also evaluated. Atorvastatin inhibited CYP3A4 enzyme activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of 48 ${\mu}M$. Compared to the controls (nicardipine alone), the area under the plasma concentration-time curve (AUC) of nicardipine was significantly (1.0 mg/kg, p<0.05) greater by 16.8-45.4%, and the peak plasma concentration ($C_{max}$) was significantly (1.0 mg/kg, p<0.05) higher by 28.0% after oral administration of nicardipine with atorvastatin, respectively. Consequently, the relative bioavailability (R.B.) of nicardipine was increased by 1.17- to 1.45-fold and the absolute bioavailability (A.B.) of nicardipine with atrovasatatin was significantly greater by 16.7-20.9% compared to that of the controls (14.3%). Compared to the i.v. control, atrovasatatin did not significantly change pharmacokinetic parameters of i.v. administration nicardipine. The enhanced oral bioavailability of nicardipine by atorvastatin suggests that CYP3A subfamily-mediated metabolism were inhibited in the intestine and/or in the liver rather than P-gp-mediated efflux of nicardipine. Based on these results, modification of nicardipine of dosage regimen is required in the patients. Human studies are required to prove the above hypothesis.

• Journal of Microbiology and Biotechnology
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• v.30 no.5
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• pp.777-784
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• 2020

Self-sufficient P450s, due to their fused nature, are the most effective tools for electron transfer to activate C-H bonds. They catalyze the oxygenation of fatty acids at different omega positions. Here, two new, self-sufficient cytochrome P450s, named 'CYP102A15 and CYP102A170,' from polar Bacillus sp. PAMC 25034 and Paenibacillus sp. PAMC 22724,respectively, were cloned and expressed in E. coli. The genes are homologues of CYP102A1 from Bacillus megaterium. They catalyzed the hydroxylation of both saturated and unsaturated fatty acids ranging in length from C₁₂-C₂₀, with a moderately diverse profile compared to other members of the CYP102A subfamily. CYP102A15 exhibited the highest activity toward linoleic acid with K_m 15.3 μM, and CYP102A170 showed higher activity toward myristic acid with Km 17.4 μM. CYP10A170 also hydroxylated the Eicosapentaenoic acid at ω-1 position only. Various kinetic parameters of both monooxygenases were also determined.

• Korean Journal of Clinical Pharmacy
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• v.22 no.1
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• pp.1-8
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• 2012

항혈소판제인 티크로피딘과 항고혈압제인 니칼디핀과의 약동학적 상호작용 연구를 위하여 티크로피딘 (3 또는 10 mg/kg)과 니칼디핀의 경구 (4 mg/kg) 및 정맥 (12 mg/kg) 투여하여 본 연구를 시행하였다. 연구방법: 티크로피딘이 cytochrome P450 (CYP) 3A4 활성과 P-glycoprotein (P-gp)의 활성에 미치는 영향도 평가하였다. 결 과: 티크로피딘과 니칼디핀의 병용투여 시 티크로피딘이 니칼디핀의 약물동태 파라미터에 미치는 결과는 다음과 같다. 티크로피딘은 CYP3A4 효소의 활성을 저해 하였으나 P-gp활성에는 영향을 미치지 못하였다. 니칼디핀의 혈중농도곡선하면적 (AUC)는 대조군에 비해 티크로피딘 10 mg/kg 병용투여군에서 유의성 (p < 0.05)있게 증가되었다. 상대적 생체이용률 (RB)은 티크로피딘 병용투여군에서 115-143%로 증가하였다. 결 론: 본 논문에서 흰쥐에 티크로피딘과 니칼디핀을 병용경구투여 시 니칼디핀의 생체이용률 (bioavailability)이 유의성 (p < 0.05)있게 증가된 것은 티크로피딘이 대사효소인 CYP3A4를 억제하여 소장과 간장에서 초회통과효과 (first-pass metabolism)를 감소 시켰기 때문인 것으로 사료된다. 본 실험결과를 토대로 인체에서 티크로피딘과 니칼디핀의 상호작용을 검토한 후 투여용량을 조절하는 것이 바람직하다고 사료된다.

• Journal of Life Science
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• v.20 no.5
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• pp.799-804
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• 2010

In humans, CYP2C19, a member of the cytochrome P450 subfamily, metabolizes arachidonic acid to produce epoxyicosanoid acids, which are involved in vascular tone and regulation of blood pressure (BP). Recent findings suggest that CYP2C19 gene polymorphisms might be considered as a novel candidate gene for cardiovascular disease. We thus focused on the Korean population to explore the association of two polymorphisms ($CYP2C19^*2$ and $^*3$) in this gene and essential hypertension (EH). A total of 1,241 participants (537 hypertensive subjects and 704 healthy controls) were recruited from the Yonsei Cardiovascular Genome Center in Korea. The CYP2C19 polymorphisms were genotyped using the $SNaPShot^{TM}$ assay. The allele and genotype frequencies of $CYP2C19^*3$ showed significant difference between hypertensives and normotensives (P=0.019 and P=0.023, respectively). Logistic regression analysis indicated that the $CYP2C19^*3$ A allele carriers were significantly associated with EH (OR, 0.723; 95% CI, 0.538-0.972, P=0.032) under a dominant model. In addition, CYP2C19 G-A haplotype ($2C19^*2\;G-^*3$ A combination) was found to significantly reduce EH risk (OR, 0.714, P=0.015). We believe this provides evidence that $CYP2C19^*3$ polymorphism may contribute to a protective effect in the development of EH.

• Biomolecules & Therapeutics
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• v.19 no.3
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• pp.364-370
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• 2011

The purpose of this study was to investigate the effects of curcumin on the pharmacokinetics of loratadine in rats. The effect of curcumin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was evaluated. Pharmacokinetic parameters of loratadine were also determined after oral and intravenous administration in the presence or absence of curcumin. Curcumin inhibited CYP3A4 activity with an IC50 value of 2.71 ${\mu}M$ and the relative cellular uptake of rhodamine-123 was comparable. Compared to the oral control group, curcumin significantly increased the area under the plasma concentration-time curve and the peak plasma concentration by 39.4-66.7% and 34.2-61.5%. Curcumin also significantly increased the absolute bioavailability of loratadine by 40.0-66.1% compared to the oral control group. Consequently, the relative bioavailability of loratadine was increased by 1.39- to 1.67-fold. In contrast, curcumin had no effect on any pharmacokinetic parameters of loratadine given intravenously, implying that the enhanced oral bioavailability may be mainly due to increased intestinal absorption caused via P-gp and CYP3A4 inhibition by curcumin rather than to reduced renal and hepatic elimination of loratadine. Curcumin enhanced the oral bioavailability of loratadine in this study. The enhanced bioavailability of loratadine might be mainly attributed to enhanced absorption in the gastrointestinal tract via the inhibition of P-gp and reduced fi rst-pass metabolism of loratadine via the inhibition of the CYP3A subfamily in the small intestine and/or in the liver by curcumin.

• Journal of Pharmaceutical Investigation
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• v.40 no.5
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• pp.291-296
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• 2010

This study was to investigate the effect of baicalein, an antioxidant, on the bioavailability of nicardipine after orally or intravenously administered nicardipine in rats. Nicardipine was administered orally (12 mg/kg) or intravenously (4 mg/kg) with or without orally administered baicalein (0.4, 2 or 10 mg/kg) to rats. In the inhibitory effect of baicalein on CYP3A4 activity, baicalein inhibited CYP3A4 activity with $IC_{50}$ values of 9.2 ${\mu}M$. The cell-based P-gp activity test using rhodamine-123 also showed that baicalein (30-10 ${\mu}M$, p<0.01) significantly inhibited P-gp activity. Compared with the control group (given nicardipine alone), the area under the plasma concentration-time curve (AUC) was significantly (2 mg/kg, P<0.05; 10 mg/kg, P<0.01) increased by 25.9-60.0%, and the peak concentration ($C_{max}$) was significantly (10 mg/kg, P<0.01) increased by 40.0% in the presence of baicalein after orally administration of nicardipine. Consequently, the relative bioavailability (R.B.) of nicardipine was increased by 1.26- to 1.60-fold and the absolute bioavailability (A.B.) was significantly (2 mg/kg, P<0.05; 10 mg/kg, P<0.01) increased by 26.0-59.9%. Compared to the i.v. control, baicalein did not significantly change pharmacokinetic parameters of nicardipine in i.v. administration. Accordingly, the enhanced oral bioavailability of nicardipine might be mainly due to increased intestinal absorption caused by P-gp inhibition rather than to reduced elimination of nicardipine by baicalein. The increase in the oral bioavailability might be mainly attributed to enhanced absorption in the small intestine via the inhibition of P-gp and reduced first-pass metabolism of nicardipine via the inhibition of the CYP3A subfamily in the small intestine and/or in the liver by baicalein. Based on these results, nicardipine dosage should be adjusted when given concomitantly with baicalein.

• Biomedical Science Letters
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• v.18 no.1
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• pp.1-9
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• 2012

Differentially expressed genes by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were identified in order to evaluate them as dioxin-sensitive markers and crucial signaling molecules to understand dioxin-induced toxic mechanisms in human bronchial cells. Gene expression profiling was analyzed by cDNA microarray and ten genes were selected for further study. They were cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1), S100 calcium binding protein A8 (calgranulin A), S100 calcium binding protein A9 (calgranulin B), aldehyde dehydrogenase 1 family, member A3 (ALDH6) and peroxiredoxin 5 (PRDX5) in up-regulated group. Among them, CYP1B1 was used as a hallmark for dioxin and sharply increased by TCDD exposure. Down-regulated genes were IK cytokine, interferon-induced protein with tetratricopeptide repeats 1 (IFIT1), nuclease sensitive element binding protein 1 (NSEP1), protein tyrosine phosphatase type VI A, member 1 (PTP4A1), ras oncogene family 32 (RAB32). Although up-regulated 4 genes in microarray were coincided with northern hybridization, down-regulated 5 genes showed U-shaped expression pattern which is sharply decreased at lower doses and gradually increased at higher doses. These results introduce some of TCDD-responsive genes can be sensitive markers against TCDD exposure and used as signaling cues to understand toxicity initiated by TCDD inhalation in pulmonary tissues.

• Journal of Nutrition and Health
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• v.50 no.3
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• pp.217-224
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• 2017

Purpose: Although it is well known thatmortality and morbidity due to cardiovascular diseases are higher in salt-sensitive subjects than in salt-resistant subjects, their underlying mechanisms related to obesity remain unclear. Here, we focused on salt-sensitive gene variants unrelated to monogenic obesity that interacted with sodium intake in humans. Methods: This review was written based on the modified $3^rd$ step of Khans' systematic review. Instead of the literature, subject genes were based on candidate genes screened from our preliminary Genome-Wide Association Study (GWAS). Finally, literature related to five genes strongly associated with salt sensitivity were analyzed to elucidate the mechanism of obesity. Results: Salt sensitivity is a measure of how blood pressure responds to salt intake, and people are either salt-sensitive or salt-resistant. Otherwise, dietary sodium restriction may not be beneficial for everyone since salt sensitivity may be associated with inherited susceptibility. According to our previous GWAS studies, 10 candidate genes and 11 single nucleotide polymorphisms (SNPs) associated with salt sensitivity were suggested, including angiotensin converting enzyme (ACE), ${\alpha}$-adducin1 (ADD1), angiotensinogen (AGT), cytochrome P450 family 11-subfamily ${\beta}$-2 ($CYP11{\beta}$-2), epithelial sodium channel (ENaC), G-protein b3 subunit (GNB3), G protein-coupled receptor kinases type 4 (GRK4 A142V, GRK4 A486V), $11{\beta}$-hydroxysteroid dehydrogenase type-2 (HSD $11{\beta}$-2), neural precursor cell-expressed developmentally down regulated 4 like (NEDD4L),and solute carrier family 12(sodium/chloride transporters)-member 3 (SLC 12A3). We found that polymorphisms of salt-sensitive genes such as ACE, $CYP11{\beta}$-2, GRK4, SLC12A3, and GNB3 may be positively associated with human obesity. Conclusion: Despite gender, ethnic, and age differences in genetics studies, hypertensive obese children and adults who are carriers of specific salt-sensitive genes are recommended to reduce their sodium intake. We believe that our findings can contribute to the prevention of early-onset of chronic diseases in obese children by facilitating personalized diet-management of obesity from childhood to adulthood.

• Biomolecules & Therapeutics
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• v.18 no.4
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• pp.469-476
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• 2010

This study was to investigate the effect of apigenin on the bioavailability of paclitaxel after oral and intravenous administration in rats. The effect of apigenin on P-glycoprotein (P-gp), cytochrome P450 (CYP)3A4 activity was evaluated. The pharmacokinetic parameters of paclitaxel were determined in rats after oral (40 mg/kg) or intravenous (5 mg/kg) administration of paclitaxel with apigenin (0.4, 2 and 8 mg/kg) to rats. Apigenin inhibited CYP3A4 activity with 50% inhibition concentration ($IC_{50}$) of 1.8 ${\mu}M$. In addition, apigenin significantly inhibited P-gp activity. Compared to the control group, apigenin significantly increased the area under the plasma concentration-time curve (AUC, p<0.05 by 2 mg/kg, 59.0% higher; p<0.01 by 8 mg/kg, 87% higher) of oral paclitaxel. Apigenin also significantly (p<0.05 by 2 mg/kg, 37.2% higher; p<0.01 by 8 mg/kg, 59.3% higher) increased the peak plasma concentration ($C_{max}$) of oral paclitaxel. Apigenin significantly increased the terminal half-life ($t_{1/2}$, p<0.05 by 8 mg/kg, 34.5%) of oral paclitaxel. Consequently, the absolute bioavailability (A.B.) of paclitaxel was significantly (p<0.05 by 2 mg/kg, p<0.01 by 8 mg/kg) increased by apigenin compared to that in the control group, and the relative bioavailability (R.B.) of oral paclitaxel was increased by 1.14- to 1.87-fold. The pharmacokinetics of intravenous paclitaxel were not affected by the concurrent use of apigenin in contrast to the oral administration of paclitaxel. Accordingly, the enhanced oral bioavailability by apigenin may be mainly due to increased intestinal absorption caused via P-gp inhibition by apigenin rather than to reduced renal and hepatic elimination of paclitaxel. The increase in the oral bioavailability might be mainly attributed to enhanced absorption in the gastrointestinal tract via the inhibition of P-gp and reduced first-pass metabolism of paclitaxel via the inhibition of the CYP3A subfamily in the small intestine and/or in the liver by apigenin. It appears that the development of oral paclitaxel preparations as a combination therapy is possible, which will be more convenient than the i.v. dosage form.