• Food Science and Biotechnology
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• 제14권2호
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• pp.297-300
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• 2005

Effects of allyl sulfides on kinetic behavior of cytochrome P450 1 (CYP1)-catalyzed ethoxyresorufin O-deethylase (EROD) activity were studied using microsomes from benzo[a]pyrene-treated human hepatoma cells. Apparent $K_m$ and $V_{max}$ values were calculated as $2.8\;{\mu}M$ and $3.0\;{\mu}mol$ resorufin/min/mg protein based on Lineweaver-Burk plot of microsomal EROD activity, respectively. Diallyl disulfide (DADS) and diallyl trisulfide (DATS) affected $K_m$ and $V_{max}$ values of EROD activity and acted as mixed-type inhibitors for CYP1 isozymes. Apparent Ki values of DADS and DATS were calculated as 1.07 and 0.88 mM, respectively, by re-plotting slopes of Lineweaver-Burk plot and inhibitor concentrations.

• 환경생물
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• 제22권1호
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• pp.177-183
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• 2004

유기주석화합물인 tributyltin chloride (TBTC), tributyltin oxide (TBTO)와 triphenyltin chloride (TPTC)를 넙치 간장으로 만든 미크로좀에 in vitro적으로 노출시켜서 이들 화합물의 대사에 관여하는 mixed function oxidase (MFO) 중 cytochrome P450 (CYP) 농도와 7-ethoxyresorufin deethylase (EROD) 활성의 변화를 조사하였으며, 또한 in vivo 실험에서는 TPTC를 넙치에게 복강주사(7.5 mg $kg^{-1}$ BW)하여 간장의 MFO (CYP농도, NADPH cytochrome c 환원효소 활성, NADH chtochrome b5 환원 효소 활성, EROD 활성) 반응을 경시적으로 조사하였다. 그 결과, in vitro에서는 TBTC, TBTO 및 TPTC가 모두 CYP 농도와 EROD 활성을 저해하였으며, 저해력은 TPTC가 가장 컸고 이어서 TBTO, TBTC의 순이었다. 유기주석화합물의 노출농도와 노출시간과 비례하면서 저해정도가 커졌으며, 특히 EROD활성의 저해는 노출농도에 크게 의존적이었다. 그리고 in vivo실험에서도 유기주석 화합물은 CYP농도, NADPH cytochrome c 환원효소 활성, NADH cytochrome b5 환원효소 활성, EROD 활성을 억제하였다. EROD 활성은 오염물질에 의한 반응이 민감하고 재현성도 있어 바람직한 측정지표로 이용될 수가 있을 것이다.

• Biomolecules & Therapeutics
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• 제28권4호
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• pp.361-369
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• 2020

Tofacitinib, a Janus kinase inhibitor, was developed for the treatment of rheumatoid arthritis. Recently, it has been associated with an increased change in arthritis development in patients with diabetes. Herein, we evaluated the pharmacokinetics of tofacitinib after intravenous (10 mg/kg) and oral (20 mg/kg) administration to rats with streptozotocin-induced diabetes mellitus and control rats. Following intravenous administration of tofacitinib to rats with streptozotocin-induced diabetes mellitus, area under the plasma concentration-time curve from time zero to infinity of tofacitinib was significantly smaller (33.6%) than that of control rats. This might be due to the faster hepatic intrinsic clearance (112%) caused by an increase in the hepatic cytochrome P450 (CYP) 3A1(23) and the faster hepatic blood flow rate in rats with streptozotocin-induced diabetes mellitus than in control rats. Following oral administration, area under the plasma concentration-time curve from time zero to infinity of tofacitinib was also significantly smaller (55.5%) in rats with streptozotocin-induced diabetes mellitus than that in control rats. This might be due to decreased absorption caused by the higher expression of P-glycoprotein and the faster intestinal metabolism caused by the higher expression of intestinal CYP3A1(23), which resulted in the decreased bioavailability of tofacitinib (33.0%) in rats with streptozotocin-induced diabetes mellitus. In summary, our findings indicate that diabetes mellitus affects the absorption and metabolism of tofacitinib, causing faster metabolism and decreased intestinal absorption in rats with streptozotocin-induced diabetes mellitus.

• 한국임상약학회지
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• 제33권4호
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• pp.242-253
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• 2023

Background: Arrhythmia due to QT prolongation is one of the most serious adverse events with drug interactions in the elderly. This study aimed to examine the incidence of arrhythmia in Korean elderly patients who administered both cytochrome P450 3A4 (CYP3A4) substrates and inhibitors. Methods: Patients using CYP3A4 substrate and inhibitor were selected from the 2017 elderly patient dataset (the Korean Health Insurance Review and Assessment Service - Aged Population Sample). Selection criteria were patients with a medication possession ratio over 80%, medication duration of at least 7 days, and a follow-up period of 3 months or more. The patient's basic information is age, gender, health insurance type, and comorbidities. The top 50 drug pairs and comorbidity with high-incidence arrhythmia were presented. Results: In patients with drug combinations for over 7 days, there were 981 incidences of arrhythmia, and 351 incidences in those with combinations for over 30 days. The comorbidities of congestive heart failure and myocardial infarction had a significant association with incidence of arrhythmia. Among patients with 7 days or longer, the drug pairs [substrates-inhibitors] with significant adjusted odds ratio (aOR) were [propranolol-cimetidine] (aOR, 2.25; 95% confidence interval [CI], 1.66-3.04). Among patients with 30 days or longer, the drug pairs with significant aOR were [tramadol-amiodarone] (aOR, 2.87; 95% CI, 1.97-4.19). Conclusions: In elderly patients, the incidence of arrhythmia was high with drug interactions of CYP3A4 substrates and inhibitors. The comorbidity of congestive heart failure was the risk factor.

• 한국해양바이오학회지
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• 제1권3호
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• pp.213-217
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• 2006

본 연구는 황백에 함유되어 있는 주요 화합물인 berberine, palmatine, limonin 및 rutaecarpine의 CYP2D6 및 p-glycoprotein 활성에 대한 저해정도를 탐색함으로써, 황백을 다른 양약과 병용시 약물상호작용을 유발할 수 있는 가능성을 평가하고자 하였다. 인체 간 마이크로좀 시료에 CYP2D6 동효소의 기질약물인 dextromethorphan과 NADPH 재생성계 및 저해제 ($200{\mu}M$)를 첨가한 후 반응시켜 생성된 대사물을 LC/MS/MS를 이용하여 정량하여 CYP2D6 동효소 활성의 변화를 평가하였다. 또한 약물수송단백인 p-glycoprotein의 활성은 L-MDR1 세포주를 이용한 calcein AM 축적 실험을 통하여 평가하였다. 그 결과 식물 알카로이드인 berberine에서 강력한 CYP2D6 활성 저해능을 관찰하였으며, 저해 효과는 농도 의존적으로 증가하였으며, mechanism-based 저해 기전을 나타내었다. 그러나 limonine과 rutaecarpine은 CYP2D6 저해 활성을 보이지 않았고, p-glycoprotein 기능에 대해서는 평가한 어떤 화합물도 저해 활성을 나타내지 않았다. 황백의 주요 성분인 berberine의 CYP2D6 활성 저해능을 고려할 때, 황백을 CYP2D6 기질약제와 병용시 약물상호작용을 유발할 가능성을 보여준다. 이러한 황백의 CYP2D6를 매개로한 임상적인 약물상호작용 가능성은 임상시험을 통하여 추가적인 검정이 필요할 것으로 사료된다.

• 약학회지
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• 제55권3호
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• pp.251-259
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• 2011

Cigarette smoke condensate (CSC) is known to be carcinogenic compound. CSC contains many organic compounds such as polycyclic aromatic hydrocarbons (PAHs), and heterocyclic amine compounds (HCAs). Reactive oxygen species (ROS) are also generated and induce oxidative DNA damage during the metabolism of CSC. The rat microsome mediated and DNA repair enzyme treated comet assays together with conventional comet assay were performed to evaluate the mechanisms of CSC genotoxicity. The organic extract of CSC induced oxidative and microsome mediated DNA damage. Vitamin C as a model antioxidant reduced DNA damage in endonuclease III treated comet assay. One of flavonoid, galangin as a CYP1A1 inhibitor, reduced DNA damage in the presence of S-9 mixture. The ethanol extracts of the mixed vegetables (BV) or the mixed fruits (BF) showed potent inhibitory effects against CSC induced DNA damage with oxidative DNA lesions and in the prescence of S-9 mixture. These results indicate that BV and BF could prevent CSC-induced cellular DNA damage by inhibiting oxidative stress and suppressing cytochrome P450 in mammalian cells.

• 대한약학회:학술대회논문집
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• 대한약학회 2002년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
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• pp.292.1-292.1
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• 2002

In order to understand the mechanism of action of TCDD. we have examined the effect of COX-inhibitors on cypla1 activity. We observed the effect of COX-inhibitor on EROD activity in C57BL/6 mouse in vovo. And we also evaluated the effect of COX-inhibitors on cypla1 mRNA. mouse cyplal promoter activity and EROD activity in Hepa cell. When Aspirin were pretreated with 3MC in vivo, the EROD activity that was stimulated by 3MC was inhibited. (omitted)

• Parasites, Hosts and Diseases
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• 제51권2호
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• pp.165-175
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• 2013

The fear that schistosomes will become resistant to praziquantel (PZQ) motivates the search for alternatives to treat schistosomiasis. The antimalarials quinine (QN) and halofantrine (HF) possess moderate antischistosomal properties. The major metabolic pathway of QN and HF is through cytochrome P450 (CYP) 3A4. Accordingly, this study investigates the effects of CYP3A4 inhibitor, ketoconazole (KTZ), on the antischistosomal potential of these quinolines against Schistosoma mansoni infection by evaluating parasitological, histopathological, and biochemical parameters. Mice were classified into 7 groups: uninfected untreated (I), infected untreated (II), infected treated orally with PZQ (1,000 mg/kg) (III), QN (400 mg/kg) (IV), KTZ (10 mg/kg)+QN as group IV (V), HF (400 mg/kg) (VI), and KTZ (as group V)+HF (as group VI) (VII). KTZ plus QN or HF produced more inhibition (P<0.05) in hepatic CYP450 (85.7% and 83.8%) and CYT b5 (75.5% and 73.5%) activities, respectively, than in groups treated with QN or HF alone. This was accompanied with more reduction in female (89.0% and 79.3%), total worms (81.4% and 70.3%), and eggs burden (hepatic; 83.8%, 66.0% and intestinal; 68%, 64.5%), respectively, and encountering the granulomatous reaction to parasite eggs trapped in the liver. QN and HF significantly (P<0.05) elevated malondialdehyde levels when used alone or with KTZ. Meanwhile, KTZ plus QN or HF restored serum levels of ALT, albumin, and reduced hepatic glutathione (KTZ+HF) to their control values. KTZ enhanced the therapeutic antischistosomal potential of QN and HF over each drug alone. Moreover, the effect of KTZ+QN was more evident than KTZ+HF.

• 대한약학회:학술대회논문집
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• 대한약학회 2002년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
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• pp.253.1-253.1
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• 2002

DA-8159 is a new PDEV inhibitor, synthesized by Dong-A Pharm, as an oral agent to treat male erectile dysfunction. DA-8159 and sildenafil are mainly metabolized by cytochrome P450 enzyme CYP 3A4. In this study. we compared the metabolism of DA-8159 with sildenafil in vitro and in vivo. First, we quantified the remaining gatio of original compound, DA-8159 and sidenafil., after we incubated drugs for 30 minutes with human liver microsome cytochrome P 450 3A4. (omitted)

• 한국환경성돌연변이발암원학회:학술대회논문집
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• 한국환경성돌연변이발암원학회 2004년도 춘계학술대회
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• pp.73-73
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• 2004