• 한국해양생명과학회지
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• 제7권2호
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• pp.145-153
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• 2022

수은은 생물 축적과 먹이사슬을 통한 생물 농축되며, 미량에서도 유해한 영향을 나타내기 때문에 해양 환경 내에서 중요한 문제가 되고 있다. 그러나 해양 소형 갑각류에 대한 수은의 생물 영향은 다른 금속에 비해 연구가 미흡하다. 본 연구에서는 기수산 물벼룩 Diaphanosoma celebensis을 아치사 농도(0.2, 0.4, 0.8 ㎍/l)의 무기 수은(HgCl₂)에 48시간 노출시킨 후, 대사 관련 유전자의 발현 양상을 조사하였다. 해독효소 유전자 5종(cytochrome P450; cyp360A1, cyp361A1, cyp4AP3, cyp4C122, cyp370C5)과 소화효소 6종(alpha amylase (AMY), alpha amylase related protein (AMY-like), trypsin (TRYP), chymotrypsin-like protein (CHY), lipase (LIP), pancreatic lipase-related protein (PLRP))의 유전자 발현을 quantitative real time reverse transcription polymerase chain reaction (qRT-PCR)을 이용하여 분석하였다. Cyp 유전자의 경우 clan2에 속하는 cyp370C5와 clan4에 속하는 cyp4AP3 유전자의 발현이 농도 의존적으로 유의하게 증가하였다. 한편 소화효소 유전자 중에서는 단백질 소화와 관련 있는 TRYP 유전자의 발현이 농도 의존적으로 증가하였다. 이러한 결과는 cyp370C5와 cyp4AP3가 수은 독성을 해독하는 과정에서 중요한 역할을 담당할 것으로 보이며, 수은이 소화효소 유전자의 발현을 조절함으로써 에너지 대사에 영향을 미칠 수 있음을 제시한다. 본 연구는 해양 소형 갑각류에서 수은에 대한 분자 수준의 영향을 이해하는데 도움이 될 것이다.

• Archives of Pharmacal Research
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• 제26권8호
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• pp.631-637
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• 2003

Chloroquine has been used for many decades in the prophylaxis and treatment of malaria. It is metabolized in humans through the N-dealkylation pathway, to desethylchloroquine (DCQ) and bisdesethylchloroquine (BDCQ), by cytochrome P450 (CYP). However, until recently, no data are available on the metabolic pathway of chloroquine. Therefore, the metabolic pathway of chloroquine was evaluated using human liver microsomes and cDNA-expressed CYPs. Chloroquine is mainly metabolized to DCQ, and its Eadie-Hofstee plots were biphasic, indicating the involvement of multiple enzymes, with apparent $K_m and V_{max}$ values of 0.21 mM and 1.02 nmol/min/mg protein 3.43 mM and 10.47 nmol/min/mg protein for high and low affinity components, respectively. Of the cDNA-expressing CYPs examined, CYP1A2, 2C8, 2C19, 2D6 and 3A4/5 exhibited significant DCQ formation. A study using chemical inhibitors showed only quercetin (a CYP2C8 inhibitor) and ketoconazole (a CYP3A4/5 inhibitor) inhibited the DCQ formation. In addition, the DCQ formation significantly correlated with the CYP3A4/5-catalyzed midazolam 1-hydroxylation (r=0.868) and CYP2C8-catalyzed paclitaxel 6$\alpha$-hydroxylation (r = 0.900). In conclusion, the results of the present study demonstrated that CYP2C8 and CYP3A4/5 are the major enzymes responsible for the chloroquine N-deethylation to DCQ in human liver microsomes.

• 생약학회지
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• 제34권1호통권132호
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• pp.86-90
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• 2003

For the determination of inhibiting cytochrome P450(CYP)3A4 activity, an improvement HPLC method was established by using a new internal standard and solvent system. Moreover, CYP3A4 amount for a optimum reaction of enzyme was determined by a comparative study with a variety concentration of enzyme. Using a established method, inhibitory effect of CYP3A4 that is drug metabolizing enzyme Investigated on EtOAc extracts of 5-class spices. As a result of experiment, EtOAc extract of white pepper (Piper nigrum L.) showed strong inhibitory activity. On a continuous experiment, the fraction 2, 4 and 5 of while pepper extract showed remarkable inhibitory activity. Pipeline, a main constituent of pepper was not included in these fraction. It is suggested that major compounds for the inhibitory activity of white pepper may be other ingredient that is not piperine.

• 생약학회지
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• 제50권3호
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• pp.159-164
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• 2019

Zanthoxylum Peel is widely used as a common spice for a variety of foods. In the orient, it has also been used as traditional agents for treating diseases such as indigestion. Recently, Zanthoxylum Peel has been reported to have anti-cancer activity, anti-microbial activity, and anti-inflammatory activity. Chemical components are known sanshool compounds and xanthoxylin. In this study, we were carried out to investigate the constituents of inhibiting a drug metabolizing enzyme CYP3A4 from Zanthoxylum Peel. CYP3A4 is known as an enzyme involved in drug metabolism as monooxygenase containing the heme. As a result of experiment, we found that bergapten ($IC_{50}=18.21{\mu}M$) and quercetin ($IC_{50}=17.27{\mu}M$) isolated from EtOAc extract of Zanthoxylum Peel showed remarkable CYP3A4-inhibiting activities. Structures of the isolated active compounds were established by chemical and spectroscopic means.

• Mass Spectrometry Letters
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• 제13권4호
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• pp.152-157
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• 2022

Schisandra chinensis and its fruits have been used as a traditional herbal medicine to treat liver dysfunction, fatigue, and chronic coughs. Several in vitro and in vivo studies suggested that dibenzocyclooctadiene lignans present in Schisandra fruits strongly inhibit CYP3A4 activity. However, reports on the inhibitory potential of dietary Schisandra supplements against CYP3A activity are limited despite their increasing consumption as dietary supplements. In this study, we evaluated the CYP3A-inhibitory potential of four dietary Schisandra supplements in human liver microsomes. At a concentration of 0.05 mg/mL, Schisandra supplements from Nature's Way, Swanson, Planetary Herbals, and Only Natural inhibited CYP3A activity by 93.9, 70.8, 33.6, and 24.8%, respectively. Nature's Way, which exhibited the strongest inhibition against CYP3A, had the highest contents of gomisin B and gomisin C, which potently inhibit CYP3A activity. The in vivo pharmacokinetics of this product should be examined to determine whether the clinical relevance of inhibiting CYP3A activity by dietary Schisandra supplementation.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.1
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• pp.149.3-150
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• 2003

CYP3A4 is the most abundant human CYP and oxidizes a diversity of substrates. including various drugs. steroids. and carcinogens. A variety of metal ions are known to affect microsomal monooxygenase activities. Effects of a series of divalent metal ions on the CYP3A4-catalyzed reaction of reconstituted system containing purified CYP3A4. NADPH-P450 reductase (NPR), and cytochrome b5 (b5) were examined. (omitted)

• 대한한의학회지
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• 제35권2호
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• pp.47-59
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• 2014

Objectives: Most drug interactions are attributed to the inhibition or induction of the activity of cytochrome P450s (CYP450). Although the regulation of CYP450s by drugs has been widely reported, there have been few studies on influence of traditional herbal formulas on the drug-metabolizing enzymes. Because herbal formulas have been used traditionally to treat various diseases and because herb-drug interactions are crucial factors determining therapeutic efficacies, a systematic evaluation of the effects of herbal formulas is important. Methods: The effects of Galgeun-tang (GGT, gegen tang), Gumiganghwal-tang (GMGHT, jiuweiqianghuo tang), Insampaedok-san (ISPDS, renshenbaidu powder), Samsoeum (SSE, shensu drink), Socheongryong-tang (SCRT, xiaoqinglong-tang) and Sosiho-tang (SSHT, xiaochaihu tang) that are traditional herbal formulas used to treat common cold, on drug-metabolizing enzymes were evaluated through an in vitro CYP3A4, CYP2D6, CYP2C19 and CYP2E1 inhibition assay to assess its interaction potential with synthetic drugs. The inhibitory effects of herbal formulas were characterized with $IC_{50}$ values. Results: These six herbal formulas inhibited the activities of CYP3A4, 2C19, 2D6 and 2E1, in a concentration-dependent manner. Among the six herbal formulas, GGT critically inhibited CYP2C19, CYP2D6 and CYP2E1. GMGHT also inhibited CYP2D6 and CYP2E1 to a greater extent than the other CYP450 isozymes. Additionally, SSE and SSHT may change the effects of medicines that depend primarily on the CYP2C19 and CYP2E1 pathways. On the other hand, ISPDS and SCRT were not inhibited CYP3A4, CYP2C19, CYP2D6 and CYP2E1-mediated metabolism. Conclusions: These findings provide useful information regarding the safety and effectiveness of herbal formulas.

• 약학회지
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• 제57권3호
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• pp.194-198
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• 2013

In the present study we evaluated drug-drug interaction potential of ambroxol and cetirizine mediated by inhibition of CYP isoforms including CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 using pooled human liver microsomes (HLMs). As measured by liquid chromatography-electrospray ionization tandem mass spectrometry, cetirizine and ambroxol inhibited significantly CYP2E1 but the maximal inhibition was approximately 36% at 10 ${\mu}M$ cetirizine and 28% at 3 ${\mu}M$ ambroxol. In addition, CYP2D6 activity was decreased to approximately 83% of control activity in pooled HLM incubated with 3 ${\mu}M$ ambroxol. Activities of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 were not significantly inhibited by cetirizine and ambroxol. Considering their maximal plasma concentration in human ($C_{max}$ of cetirizine is approximately 0.67 ${\mu}M$ and $C_{max}$ of ambroxol is 0.044 ${\mu}M$), these two drugs have very low possibility in drug-drug interaction by CYP inhibition in clinical situations.

• 한국임상약학회지
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• 제15권1호
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• pp.1-8
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• 2005

Clopidogrel is used to reduce the risk of cardiovascular events in patients with atherosclerosis documented by recent ischemic stroke, recent myocardial infarction (MI), or established peripheral arterial disease (secondary prevention). Clopidogrel is metabolized by CYP3A4, and the active metabolites inhibit platelet aggregation. The purpose of this study was to assess clopidogrel only versus clopidogrel + others (aspirin, CYP3A4 inhibitor, and CYPBA4 inducer) in terms of cardiovasculalr events and bleeding complications. We reviewed the charts of patients who visited between August 1, 2002 and August 31, 2003, retrospectively. Total 72 patients were included and they consisted of 5 groups; clopidogrel group (n=36), clopidogrel + aspirin group (n=11), clopidogrel + CYP3A4 inhibitor group (n=15), clopidogrel + aspirin + CYP3A4 inhibitor group (n=6), clopidorel + CYP3A4 inducer group (n=4). The primary endpoints at 6 months, 12 months were the composite of cardiovascular (CV) events. The secondary end-point was the incidence of bleeding events at 6months, and 12months. At 12months, the primary endpoint was not significantly different among the five groups (p=0.056). In comparison of two groups as clopidogrel only versus clopidogrel + others (aspirin, CYP3A4 inhibitor and CYP3A4 inducer), the primary endpoint was significantly different (p=0.02). The CV events were increased in the clopidogrel + others group. The secondary end point was not significantly different among the five groups (p=0.52). However, time to bleeding events was 230.8 in the clopidogrel group and 74.7 in the clopidogrel + others group (p = 0.046). In conclusion, clopidogrel interaction with aspirin, CYP3A4 inhibitor, and CYP3A4 inducer affected cardiovascular events and bleeding events. Drug interaction of clopidogrel with concurrent medications should be considered cautiously.

• Journal of Microbiology and Biotechnology
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• 제30권8호
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• pp.1207-1213
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• 2020

Aflatoxin B1 (AFB1) is a mycotoxin produced by Aspergillus flavus (A. flavus). AFB1 is reported to have high thermal stability and is not decomposed by heat treatment during food processing. Therefore, in this study, knowing that AFB1 is metabolized by cytochrome P450 (CYP), our aim was to develop a method to detoxify A. flavus-contaminated maize, under normal temperature and pressure, using Escherichia coli expressing human CYP3A4. First, the metabolic activity of AFB1 by recombinant human CYP3A4 was evaluated. As a result, we confirmed that recombinant human CYP3A4 metabolizes 98% of AFB1. Next, we found that aflatoxin Q1, a metabolite of AFB1 was no longer mutagenic. Furthermore, we revealed that about 50% of the AFB1 metabolic activity can be maintained for 3 months when E. coli expressing human CYP3A4 is freeze-dried in the presence of trehalose. Finally, we found that 80% of AFB1 in A. flavus-contaminated maize was metabolized by E. coli expressing human CYP3A4 in the presence of surfactant triton X-405 at a final concentration of 10% (v/v). From these results, we conclude that AFB1 in A. flavus-contaminated maize can be detoxified under normal temperature and pressure by using E. coli expressing human CYP3A4.