• Biomolecules & Therapeutics
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• 제19권2호
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• pp.237-242
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• 2011

This study was designed to investigate the effects of glipizide on the pharmacokinetics of carvedilol after oral or intravenous administration of carvedilol in rats. Clinically carvedilol and glipizide can be prescribed for treatment of cardiovascular diseases as the complications of diabetes, and then, Carvedilol and glipizide are all substrates of CYP2C9 enzymes. Carvedilol was administered orally or intravenously without or with oral administration of glipizide to rats. The effects of glipizide on cytochrome P450(CYP) 2C9 activity and P-gp activity were also evaluated. Glipizide inhibited CYP2C9 activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of 18 ${\mu}M$. Compared with the control group, the area under the plasma concentration-time curve (AUC) was significantly increased by 33.0%, and the peak concentration ($C_{max}$) was significantly increased by 50.0% in the presence of glipizide after oral administration of carvedilol. Consequently, the relative bioavailability (R.B.) of carvedilol was increased by 1.13- to 1.33-fold and the absolute bioavailability (A.B.) of carvedilol in the presence of glipizide was increased by 36.8%. After intravenous administration, compared to the control, glipizide could not significantly change the pharmacokinetic parameters of carvedilol. Therefore, the enhanced oral bioavailability of carvedilol may mainly result from inhibition of CYP2C9-mediated metabolism rather than both P-gp-mediated effl ux in the intestinal or in the liver and renal elimination of carvedilol by glipizide.

• Toxicological Research
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• 제15권1호
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• pp.89-93
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• 1999

2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD) is known to induce cytochrome p450 1A1 and to activate c-Src kinase and p21 Ras. This study examined the molecular interactions of adaptor proteins including Shc, Grb2, and Sos in rat primary hepatocytes and their relationship to the induction of CYP1A1 by TCDD. TCDD induced CYP1A1 level and EROD activity in a dose-dependent mode. Sos/Grb2 association isincreased by TCDDㅑㅜ a dose dependent mode. Tyrosine phosphorylated Shc, mainly p152, onloads to Grb2/Sos complex upon TCDD stimulation. The electrophoretic mobility shift of Sos is showed by TCDD. These results indicate that TCDD modulated the molecular interaction features of adaptor compoes proteins including Shc, Grb2, and Cnl in early signaling pathway of TCDD-mediated CYP 1A1 induction of rat primary hepatocyte.

• 생명과학회지
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• 제17권3호통권83호
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• pp.334-339
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• 2007

본 연구는 우황청심원을 비롯한 상용되는 20종의 한약제제를 대상으로 9종의 시토크롬 동종효소에 대한 대사능의 저해정도를 고속 스크리닝 기법을 이용하여 탐색함으로써, 한약제제와 약물의 병용으로 인한 약물 상호작용 가능성을 평가하고자 하였다. 인체 간 마이크로좀 시료에 9종의 주요 시토크롬 약물대사효소의 지표약물과NADPH-generating system및 한약제제(500 ${\mu}g/ml$)를 첨가한 후 $37^{\circ}C$에서 15분간 반응시켜 생성된 각각의 대사물을 LC/MS/MS를 이용하여 정량하여 시토크롬 동종효소 활성의 변화를 평가하였다. 그 결과 우황청심원 현탁액 및 황련해독탕 물 추출물이 각각 CYP2B6 및 CYP2D6 효소 활성을 선택적으로 강력하게 저해하였다. 이러한 결과는 약국에서 쉽게 구입할 수 있는 한약제제들 중 일부는 인체 간 시토크롬 활성 저해능을 가지고 있고, 이들 효소에 의해 대사되는 약물과의 병용 복용시 약물상호작용 발생 가능성이 있음을 의미한다. 향후 한약제제에서 저해능을 나타내는 주된 성분을 규명하여 이 성분의 저해능과 저해 기전을 살피는 노력이 필요할 것이다.

• Asian Pacific Journal of Cancer Prevention
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• 제15권17호
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• pp.7377-7381
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• 2014

CYP2E1 PstI polymorphism G-1259C (rs3813867) genotype distributions vary significantly among different populations and are associated with both diseases, like cancer, and adverse drug effects. To date, there have been limited genotype distributions and allele frequencies of this polymorphism reported in the three major indigenous ethnic groups (KadazanDusun, Bajau, and Rungus) in Sabah, also known as North Borneo. The aim of this study was to investigate the genotype distributions and allele frequencies of the CYP2E1 PstI polymorphism G-1259C in these three major indigenous peoples in Sabah. A total of 640 healthy individuals from the three dominant indigenous groups were recruited for this study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) at G-1259C polymorphic site of CYP2E1 gene was performed using the Pst I restriction enzyme. Fragments were analyzed using agarose gel electrophoresis and confirmed by direct sequencing. Overall, the allele frequencies were 90.3% for c1 allele and 9.7% for c2 allele. The genotype frequencies for c1/c1, c1/c2 and c2/c2 were observed as 80.9%, 18.8%, and 0.3%, respectively. A highly statistical significant difference (p<0.001) was observed in the genotype distributions between indigenous groups in Sabah with all Asian and non-Asian populations. However, among these three indigenous groups, there was no statistical significant difference (p>0.001) in their genotype distributions. The three major indigenous ethnic groups in Sabah show unique genotype distributions when compared with other populations. This finding indicates the importance of establishing the genotype distributions of CYP2E1 PstI polymorphism in the indigenous populations.

• Mycobiology
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• 제47권3호
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• pp.301-307
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• 2019

The $11{\alpha}$-hydroxylation of $16{\alpha}$, 17-epoxyprogesterone (EP) catalyzed by Rhizopus nigricans is crucial for the steroid industry. However, lower conversion rate of the biohydroxylation restricts its potential industrial application. The $11{\alpha}$-steroid hydroxylase CYP509C12 from R. oryzae were reported to play a crucial role in the $11{\alpha}$-hydroxylation in recombinant fission yeast. In the present study, the CYP509C12 of R. oryzae (RoCYP) was introduced into R. nigricans using the liposome-mediated mycelial transformation. Heterologous expression of RoCYP resulted in increased fungal growth and improved intracellular reactive oxygen species content in R. nigricans. The $H_2O_2$ levels in RoCYP transformants were approximately 2-folder that of the R. nigricans wild type (RnWT) strain, with the superoxide dismutase activities increased approximately 45% and catalase activities decreased approximately 68%. Furthermore, the $11{\alpha}$-hydroxylation rates of EP in RoCYP transformants (C4, C6 and C9) were 39.7%, 38.3% and 38.7%, which were 12.1%, 8.2% and 9.4% higher than the rate of the RnWT strain, respectively. This paper investigated the effect of heterologous expression of RoCYP in R. nigricans, providing an effective genetic method to construct the engineered strains for steroid industry.

• Asian Pacific Journal of Cancer Prevention
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• 제16권8호
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• pp.3559-3563
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• 2015

The aim of the present study was to evaluate the relative contribution of CYP1A2 isoforms (-3860 G/A, -2467T/delT and -163C/A) in control subjects and breast cancer patients to the metabolism of caffeine in human liver. Restriction fragment length polymorphism analysis of PCR-amplified Fragments (PCR-RFLP) was used for the genotyping of CYP1A2 SNPs and HPLC allowed the phenotyping through the measurement of CYP1A2 activity using the 17X + 13X + 37X/137X urinary metabolite ratio (CMR) and plasma caffeine half life (T1/2). The CYP1A2 -3860A genotype was associated with a decreased risk of breast cancer. In contrast, distributions of the CYP1A2 -2467T/delT or -2467delT/delT and -163A/C or A/A genotypes among breast cancer patients and controls were similar. When the genotype and phenotype relationship was measured by comparing the mean CMR ratios and caffeine half life within the genotype groups between subjects and breast cancer patients, there were no significant differences except for -3860 A, most of them being homozygous for the -3860 G/G SNP and had a significant higher mean CMR ratio and half life than those with -3860 G/A (P=0.02). The results of this preliminary study show a significant association between CP1A2 -3860 G variant and CYP1A2 phenotype which must be confirmed by further large-size case-control studies.

• 생명과학회지
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• 제22권8호
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• pp.1057-1063
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• 2012

간질은 가장 흔한 만성 신경 장애로 70% 이상의 환자에서 항전간제로 증상의 조절이 가능하다. 약물의 치료효과를 예측하는데 있어 개인이 가진 유전적 다형성이 부분적인 영향을 주는 것으로 알려지면서 항전간제의 효과에 영향을 주는 유전자 연구가 빠르게 진행되고 있다. 본 연구에서는 83명의 간질 환자를 대상으로 간질 환자의 약물대사와 관련된 것으로 알려진 유전자(CYP2C9, CYP2C19, ABCB1, SCN1A)의 다형성과 약물부작용의 관계에 대해 연구하였다. 연구 결과, 약물 이상 반응과 약물 용량의 상관관계는 통계적으로 유의한 수준은 관찰되지 않았다. 한편, carbamazepine 계열에서의 환자군에서는 SCN1A 유전자의 인트론 유전자 유전형 CC와 CT 유전형에 비해 TT 유전형에서 약물용량과 연관을 보였으며, 500 mg 이상의 용량을 투약한 환자에서는 TT 유전형에 비해 CC와 CT를 가진 유전형에서 통계적으로 유의한 상관성을 보였다.

• 생명과학회지
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• 제28권7호
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• pp.835-840
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• 2018

본 연구는 시토크롬 P450 단백질을 암호화하는 애기장대 유래의 AtCYP78A7을 과발현하는 형질전환 식물체로부터 AtCYP78A7 단백질을 특이적으로 인식하는 단일큰론 항체의 제조와 그 항체를 AtCYP78A7 단백질과 접촉시켜 항원-항체 복합체 형성을 검출함으로써 AtCYP78A7 단백질을 효소면역학적(ELISA) 방법으로 검출하는 진단 키트를 개발하기 위하여 수행하였다. 재조합한 GST-AtCYP78A7 단백질을 항원으로 사용하여 단일클론 항체를 분비하는 융합세포주를 제조한 후 비오틴화 및 페어링 테스트를 통해 포획항체와 검출항체를 선정하였으며, GST-AtCYP78A7 정제 단백질을 기준으로 일품벼, 화영벼, AtCYP78A7 과발현 벼(10B-5, 18A-4)의 용해물을 검출항원으로 사용하여 product test를 진행하였다. 그 결과 AtCYP78A7 단백질에 특이적으로 결합하는 4개의 단클론 항체(mAb 6A7, mAb 4C2, mAb 11H6, mAb 7E8)를 생산하였고, 포획항체 mAb 4C2와 검출항체 mAb 7E8-biotin의 조합으로 ELISA 키트를 개발하였다. 개발된 ELISA 키트를 이용한 벼 시료의 분석 결과 AtCYP78A7 과발현 벼는 전체 단백질 대비 AtCYP78A7 단백질의 비율이 0.1% 이상인 양성으로, 일품벼와 화영벼는 0.1% 미만인 음성으로 나타나 키트를 이용한 AtCYP78A7 단백질의 검출이 가능하였으며, 따라서 본 키트는 향후 AtCYP78A7를 과발현하는 형질전환 작물을 대상으로 하는 환경 모니터링 또는 인체 위해성 평가에 유용하게 활용될 수 있을 것으로 사료된다.

• Biomolecules & Therapeutics
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• 제17권3호
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• pp.311-317
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• 2009

Ginkgo biloba (G. biloba) extract is a widely used phytomedicine for the oral treatment of peripheral vascular disease. Cilostazol is a synthetic antiplatelet and vasodilating agent for the treatment of intermittent claudication resulting from peripheral arterial disease. It is likely to use concomitantly G. biloba extract and cilostazol for the treatment of peripheral arterial disease, which raises a concern of increasing their adverse effects of herbal-drug interactions. To clarify any possible herbal-drug interaction between G. biloba extract and cilostazol, the effect of the G. biloba extract on the pharmacokinetics of cilostazol was investigated. As cilostazol is known to be eliminated mainly by cytochrome P450 (CYP)-mediated metabolism, we investigated the effects of G. biloba extract on the human CYP enzyme activities and the effect of G. biloba extract on the pharmacokinetics of cilostazol after co-administration of the two agents to male beagle dogs. The G. biloba extract inhibited more or less CYP2C8, CYP2C9, and CYP2C19 enzyme activities in the in vitro microsomal study with $IC_{50}$ values of 30.8, 60.5, and $25.2{\mu}g/ml$, respectively. In the pharmacokinetic study, co-administration with the G. biloba extract had no significant effect on the pharmacokinetics of cilostazol in dogs, although CYP2C has been reported to be responsible for the metabolism of cilostazol. In conclusion, these results suggest that there may not be a pharmacokinetic interaction between G. biloba extract and cilostazol.

• Preventive Nutrition and Food Science
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• 제19권4호
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• pp.268-273
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• 2014

The induction of detoxification enzymes by benzyl isothiocyanate (BITC) and its synthetic N-acetyl-L-cysteine (NAC) conjugate (NAC-BITC) was examined in Hepa1c1c7 murine hepatoma cells. BITC and NAC-BITC inhibited Hepa1c1c7 cell growth in a dose-dependent manner. Cell growth was 4.5~57.2% lower in Hepa1c1c7 cells treated with $0.1{\sim}1.0{\mu}M$ BITC than in control-treated Hepa1c1c7 cells. The NAC-BITC treatment had a similar inhibitory pattern on Hepa1c1c7 cell growth; $0.5{\mu}M$ and $10{\mu}M$ NAC-BITC decreased cell growth by 13.6% and 47.4%, respectively. Treatment of Hepa1c1c7 cells with $0.1{\sim}2.0{\mu}M$ BITC also elicited a dose-response effect on the induction of quinone reductase quinone reductase (QR) activity and QR mRNA expression. Treatment with $1{\mu}M$ and $2{\mu}M$ BITC caused 1.8- and 2.8-fold inductions of QR mRNA, respectively. By comparison, treatment with $1{\mu}M$ and $2{\mu}M$ NAC-BITC caused 1.6-and 1.9-fold inductions of QR mRNA, respectively. Cytochrome P450 (CYP) 1A1 and CYP2E1 induction were lower in $0.1{\sim}2{\mu}M$ BITC-treated cells than in control-treated cells. CYP2E1 activity was 1.2-fold greater in $0.1{\mu}M$ NAC-BITC-treated cells than in control-treated cells. However, the CYP2E1 activity of cells treated with higher concentrations (i.e., $1{\sim}2{\mu}M$) of NAC-BITC was similar to the activity of control-treated cells. Considering the potential of isothiocyanatesto prevent cancer, these results provide support for the use of BITC and NAC-BITC conjugates as chemopreventive agents.