• 생명과학회지
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• 제21권11호
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• pp.1558-1564
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• 2011

CYP2J2는 치료약물 및 아라키돈산과 같은 내인성 화합물의 대사에 중요한 역할을 수행하고 있는 효소이다. 최근, CYP2J2 단백질이 인체 종양 조직이나 종양 세포주에 과발현되어 있고, CYP2J2 효소의 작용에 의해 생성된 에폭시에이코사트리에논산(EETs)이 세포사멸을 방지한다는 것이 보고되었다. 본 연구는 시판중인 약물 120종을 대상으로 시토크롬 2J2 동종효소에 저해능을 가지는 화합물을 발굴하고자 하였다. 인체 간 마이크로솜 시료에 아스테미졸과 NADPH 재생성계 및 약물(50 ${\mu}M$)을 첨가한 후 15분간 반응시켜 생성된 대사물을 LC/MS/MS를 이용하여 분석하여 시토크롬 2J2 동종효소 활성의 변화를 평가하였다. 그 결과 할로페리돌, 터페나딘, 아리피프라졸, 미코나졸의 순으로 CYP2J2 효소 활성 저해능을 보였다. 미코나졸은 CYP2J2에 의해 매개되는 에바스틴($IC_{50}$=11.2 ${\mu}M$) 및 터페나딘($IC_{50}$=2.2 ${\mu}M$) 대사를 강력하게 저해하였다. 터페나딘 또한 CYP2J2 매개 에바스틴 대사를 농도 의존적으로 저해하였다($IC_{50}$=13.6 ${\mu}M$). 향후, 이들 약물을 대상으로 한 항암 활성 평가가 필요할 것으로 판단된다.

• Mass Spectrometry Letters
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• 제11권4호
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• pp.113-117
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• 2020

Cytochrome P450 2J2 (CYP2J2) is a member of the cytochrome P450 superfamily, and is known to be arachidonic acid epoxygenase that mediates the formation of four bioactive regioisomers of epoxyeicosatrienoic acids (EETs). CYP2J2 is also involved in the metabolism of drugs such as albendazole, astemizole, danazol, ebastine, and terfenadine. CYP2J2 is highly expressed in the heart and cancer tissues. In this study, the inhibitory potential of ten natural products against CYP2J2 activity was evaluated using human liver microsomes and tandem mass spectrometry. Among them, bilobetin, which is a kind of biflavonoid, exhibits a strong inhibitory effect against the CYP2J2-mediated astemizole O-demethylation (IC50 = 0.73 μM) and terfenadine hydroxylation (IC50 = 0.89 μM). This result suggests that bilobetin can be used as strong CYP2J2 inhibitor in drug metabolism study.

• 생명과학회지
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• 제23권9호
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• pp.1126-1132
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• 2013

CYP2J2 효소는 간외의 조직에 존재 하는 효소로써, 주로 심혈관계에 발현되어 있다. CYP2J2는 내인성 대사체 및 여러 치료 약물들의 대사에 중요한 작용을 하고 있다. 또한 CYP2J2는 인체의 종양조직이나 종양 세포주에서 과발현되어 있어, 종양 치료를 위한 새로운 표적이 되고 있다. 본 연구에서는 천연물 10종을 대상으로 시토크롬 2J2 동효소에 저해능을 가지는 화합물을 발굴하고자 하였다. 10종의 천연물 중 thelephoric acid는 CYP2J2에 의해 매개되는 에바스틴($IC_{50}=5.32{\mu}M$), 아스테미졸($IC_{50}3.23{\mu}M$) 및 터페나딘($IC_{50}=3.27{\mu}M$) 대사를 강력하게 저해하였다. 향후, 이 약물을 대상으로 한 항암 활성 평가가 필요할 것으로 판단된다.

• Archives of Pharmacal Research
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• 제23권4호
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• pp.267-282
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• 2000

Cytochrome P45O (CYP) 2E1 catalyzes the metabolism of a wide variety of therapeutic agents, procarcinogens, and low molecular weight solvents. CYP2E1-catalyzed metabolism may cause toxicity or DNA damage through the production of toxic metabolites, oxygen radicals, and lipid peroxidation. CYP2E1 also plays a role in the metabolism of endogenous compounds including fatty acids and ketone bodies. The regulation of CYP2E1 expression is complex, and involves transcriptional, post-transcriptional, translational, and post-translational mechanisms. CYP2E1 is transcriptionally activated in the first few hours after birth. Xenobiotic inducers elevate CYP2E1 protein levels through both increased translational efficiency and stabilization of the protein from degradation, which appears to occur primarily through ubiquitination and proteasomal degradation. CYP2E1 mRNA and protein levels are altered in response to pathophysiologic conditions by hormones including insulin, glucagon, growth hormone, and leptin, and growth factors including epidermal growth factor and hepatocyte growth factor, providing evidence that CYP2E1 expression is under tight homeostatic control.

• Journal of Ginseng Research
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• 제40권4호
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• pp.375-381
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• 2016

Background: We evaluated the drug interaction profile of Red Ginseng (RG) with respect to the activities of major cytochrome P450 (CYP) enzymes and the drug transporter P-glycoprotein (P-gp) in healthy Korean volunteers. Methods: This article describes an open-label, crossover study. CYP probe cocktail drugs, caffeine, losartan, dextromethorphan, omeprazole, midazolam, and fexofenadine were administered before and after RG supplementation for 2 wk. Plasma samples were collected, and tolerability was assessed. Pharmacokinetic parameters were calculated, and 90% confidence intervals (CIs) of the geometric mean ratios of the parameters were determined from logarithmically transformed data using analysis of variance after RG administration versus before RG administration. Results: Fourteen healthy male participants were evaluated, none of whom were genetically defined as poor CYP2C9, 2C19, and CYP2D6 metabolizers based on genotyping. Before and after RG administration, the geometric least-square mean metabolic ratio (90% CI) was 0.870 (0.805-0.940) for caffeine to paraxanthine (CYP1A2), 0.871 (0.800-0.947) for losartan (CYP2C9) to EXP3174, 1.027 (0.938-1.123) for omeprazole (CYP2C19) to 5-hydroxyomeprazole, 1.373 (0.864-2.180) for dextromethorphan to dextrorphan (CYP2D6), and 0.824 (0.658-1.032) for midazolam (CYP3A4) to 1-hydroxymidazolam. The geometric mean ratio of the area under the curve of the last sampling time ($AUC_{last}$) for fexofenadine (P-gp) was 0.963 (0.845-1.098). Administration of concentrated RG for 2 wk weakly inhibited CYP2C9 and CYP3A4 and weakly induced CYP2D6. However, no clinically significant drug interactions were observed between RG and CYP and P-gp probe substrates. Conclusion: RG has no relevant potential to cause CYP enzyme- or P-gp-related interactions.

• Journal of Ginseng Research
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• 제40권1호
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• pp.47-54
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• 2016

Background: The roots of Panax ginseng contain noble tetracyclic triterpenoid saponins derived from dammarenediol-II. Dammarene-type ginsenosides are classified into the protopanaxadiol (PPD) and protopanaxatriol (PPT) groups based on their triterpene aglycone structures. Two cytochrome P450 (CYP) genes (CYP716A47 and CYP716A53v2) are critical for the production of PPD and PPT aglycones, respectively. CYP716A53v2 is a protopanaxadiol 6-hydroxylase that catalyzes PPT production from PPD in P. ginseng. Methods: We constructed transgenic P. ginseng lines overexpressing or silencing (via RNA interference) the CYP716A53v2 gene and analyzed changes in their ginsenoside profiles. Result: Overexpression of CYP716A53v2 led to increased accumulation of CYP716A53v2 mRNA in all transgenic roots compared to nontransgenic roots. Conversely, silencing of CYP716A53v2 mRNA in RNAi transgenic roots resulted in reduced CYP716A53v2 transcription. HPLC analysis revealed that transgenic roots overexpressing CYP716A53v2 contained higher levels of PPT-group ginsenosides ($Rg_1$, Re, and Rf) but lower levels of PPD-group ginsenosides (Rb1, Rc, $Rb_2$, and Rd). By contrast, RNAi transgenic roots contained lower levels of PPT-group compounds and higher levels of PPD-group compounds. Conclusion: The production of PPD- and PPT-group ginsenosides can be altered by changing the expression of CYP716A53v2 in transgenic P. ginseng. The biological activities of PPD-group ginsenosides are known to differ from those of the PPT group. Thus, increasing or decreasing the levels of PPT-group ginsenosides in transgenic P. ginseng may yield new medicinal uses for transgenic P. ginseng.

• 한국식품영양과학회지
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• 제45권10호
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• pp.1391-1397
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• 2016

본 연구에서는 다양한 약리 활성 및 항산화 활성이 높다고 보고된 신선초 추출물을 대상으로 in vitro 및 in vivo계에서 알코올성 간세포 손상을 유도하여 그 효과를 검토하였다. 알코올 산화 효소인 cytochrome P4502E1(CYP2E1)이 과발현된 HepG2 세포에서 200 mM의 알코올과 신선초 추출물을 투여하였을 때 농도 의존적으로 세포생존률 및 catalase(CAT) 활성이 증가하였다. In vitro에서 신선초 추출물의 보호 효과를 확인한 후 7주령의 C57BL/6J 마우스에 알코올과 신선초 추출물 20, 100 mg/kg BW/d를 급여한 결과 혈중 ALT, AST, GGT의 농도는 대조군보다 유의적으로 증가한 알코올군에 비해 신선초 추출물을 급여한 군에서 유의적 감소했음을 확인할 수 있었다. 그뿐만 아니라 알코올 투여로 세포변성과 지방구가 보이는 간 조직의 변화가 신선초 투여로 의해 대조군과 유사하게 관찰되었다. 항산화 효소의 변화와 지질과산화 수준은 대조군보다 알코올군이 유의적 증가했으며, 신선초 추출물 급여군에서 감소하는 결과를 보였고, 특히 신선초 20 mg/kg BW/d로 급여한 군에서 CAT, glutathione peroxidase, glutathione reductase, malondialdehyde(MDA) 등의 유의적 감소를 보였다. 이 같은 변화를 매개했다고 생각되는 CYP2E1의 발현과 활성은 대조군보다 알코올 투여군에서 유의적으로 상승하였으며, 특히 항산화 효소와 MDA 함량에서 유의적 감소했던 20 mg/kg BW/d의 신선초 투여군에서 유의적 감소하는 것으로 나타났다. 그러므로 이는 신선초 추출물에 함유된 luteolin, quercetin, chalcone 화합물 등의 성분에 의해 알코올 유도 산화적 스트레스가 감소하였다고 생각되며, 신선초 추출물은 알코올 대사과정에서 산화적 스트레스를 억제하여 간 보호 효과가 있을 것으로 생각한다.

• Asian Pacific Journal of Cancer Prevention
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• 제13권6호
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• pp.2647-2653
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• 2012

Involvement of cytochrome P450 genes (CYPs) in breast cancer (BCa) may differ between populations, with expression patterns affected by tumorigenesis. This may have an important role in the metabolism of anticancer drugs and in the progression of cancer. The aim of this study was to determine the mRNA expression patterns of four cytochrome P450 genes (CYP2W1, 3A5, 4F11 and 8A1) in Mexican women with breast cancer. Real-time PCR analyses were conducted on 32 sets of human breast tumors and adjacent non-tumor tissues, as well as 20 normal breast tissues. Expression levels were tested for association with clinical and pathological data of patients. We found higher gene expression of CYP2W1, CYP3A5, CYP4F11 in BCa than in adjacent tissues and only low in normal mammary glands in our Mexican population while CYP8A1 was only expressed in BCa and adjacent tissues. We found that Ki67 protein expression was associated with clinicopathological features as well as with CYP2W1, CYP4F11 and CYP8A1 but not with CYP3A5. The results indicated that breast cancer tissues may be better able to metabolize carcinogens and other xenobiotics to active species than normal or adjacent non-tumor tissues.

• 대한예방의학회:학술대회논문집
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• 대한예방의학회 2000년도 제52차 추계학술대회 연제집
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• pp.23-24
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• 2000

• Asian Pacific Journal of Cancer Prevention
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• 제13권3호
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• pp.837-846
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• 2012

Breast cancer (BCa) is the leading type of cancer in Mexican women. Genetic factors, such as single nucleotide polymorphisms (SNP) of P450 system, have been reported in BCa. In this report, and for the first time in the literature, we analyzed the rs3735684 (7021 G>A), rs11553651 (15016 G>T) and rs56195291 (60020 C>G) polymorphisms in the CYP2W1, 4F11 and 8A1 genes in patients with BCa and in healthy Mexican women to identify a potential association between these polymorphisms and BCa risk. Patients and controls were used for polymorphism analysis using an allelic discrimination assay with TaqMan probes and confirmed by DNA sequencing. Links with clinic-pathological characteristics were also analyzed. Statistical analysis was performed using the standard ${\chi}^2$ or Fisher exact test statistic. No significant differences were observed in the distributions of CYP2W1 (OR 8.6, 95%CI 0.43-172.5 P>0.05; OR 2.0, 95%CI 0.76-5.4, P>0.05) and CYP4F11 (OR 0.3, 95%CI 0.01-8.4 P>0.05) genotypes between the patients and controls. Only the CYP8A1 CC genotype was detected in patients with BCa and the controls. All polymorphism frequencies were in Hardy-Weinberg Equilibrium (HWE) in the controls (P>0.05). We found a significant association between BCa risk and smoking, use of oral contraceptives or hormonal replacement therapy (HRT), obesity, hyperglycemia, chronic diseases, family history of cancer and menopausal status in the population studied (P<0.05). Tobacco, oral contraceptive or HRT, chronic diseases and obesity or overweight were strongly associated with almost eight, thirty-five, nine and five-fold increased risk for BCa. Tobaco, obesity and hyperglycemia significantly increased the risk of BCa in the patients carrying variant genotypes of CYP2W1 (P<0.05). These results indicate that the CYP2W1 rs3735684, CYP4F11 rs11553651 and CYP8A1 rs56195291 SNPs are not a key risk factor for BCa in Mexican women. This study did not detect an association between the CYP2W1, 4F11 and 8A1 genes polymorphisms and BCa risk in a Mexican population. However, some clinico-pathological risk factors interact with CYP2W1 genotypes and modifies susceptibility to BCa.