• Journal of Pharmaceutical Investigation
• /
• 제33권4호
• /
• pp.305-310
• /
• 2003

One of the possible mechanisms of multi-drug resistance found in cancer cells is the over-expression of P­glycoprotein (P-gp). Studies have shown that compounds in plants including vegetables and fruits not only have anticancer activities but may also modulate P-gp activity. The effect of flavonoids and organic isothiocyanate on P-gp activity was studied in human uterine sarcoma cell lines, MES-SA (sensitive) and MES-SA/DX5 (resistant) cells. The accumulation of daunomycin (DNM), a P-gp substrate, was approximately 10 times greater in the sensitive cell as compared to the resistant cells over the entire time course (up to 2 hours). The positive control, verapamil increased the two hour accumulation of DNM while quercetin decreased that of DNM in the resistant cells. 1-Naphtyl-isothiocyanate (NITC) showed no effect on the two hour accumulation of DNM. The $IC_{50}$ values for DNM in the resistant cells was about 20 times higher than that observed in the sensitive cells $(10.1{\pm}1.7\;{\mu}M\;vs.\;0.58{\pm}0.28\;{\mu}M)$. Verapamil reduced the $IC_{50}$ value for DNM whereas flavonoids (quercetin and fisetin) increased those for DNM in the resistant cells.

• Journal of Pharmaceutical Investigation
• /
• 제35권4호
• /
• pp.249-254
• /
• 2005

Multidrug resistance (MDR) of cancer cells is, at least in part, associated with the overexpression of P-glycoprotein (P-gp). Many studies have demonstrated that natural compounds obtained from fruits, vegetables, teas and medicinal plants may modulate P-gp activity. The objective of the present investigation was to examine the effect of seven natural compounds on the P-gp activity in human uterine sarcoma cell line, MES-SA/DX5. Daunomycin uptake was significantly increased by biochanin A and silymarin (p<0.0001) whereas it was reduced by morin (p<0.01). The efflux of daunomycin from the cells was significantly inhibited by biochanin A, morin, cephalotaxine, berberine (p<0.05) and silymarin (p<0.0001). Biochanin A, berberine and silymarin significantly decreased $IC_{50}$ value of daunomycin (p<0.05) while morin increased it (p<0.05). These results suggest that some natural compounds such as biochanin A and silymarin may inhibit P-gp function and can be developed as MDR reversing agents to improve the efficacy of chemotherapeutic drugs when administered concomitantly.

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

• 생명과학회지
• /
• 제18권9호
• /
• pp.1244-1248
• /
• 2008

본 연구에서는 다양한 천연 추출물의 P-gp 저해능의 고속 탐색을 통하여 새로운 화학감작제 후보물질을 발굴하고자 하였다. P-gp 활성에 대한 천연 추출물의 저해능은 P-gp이 과발현된 L-MDR1 세포주를 이용하여 대표적인 P-gp 기질 약물인 calcein AM의 세포 내 축적 정도를 측정함으로써 평가하였다. 강황 및 울금은 가장 강력한 P-gp 기능 저해를 나타내었고, 이외에도 Mentrasto, 취호초, 봉출, Rakta chandan, 강진향, 소목, 노회 등의 순으로 P-gp 기능 저해능을 보였다. 이들 추출물에서 P-gp 저해능을 보이는 성분을 확인하기 위하여 LC/MS/MS 분석을 수행한 결과, 기존에 P-gp 활성을 저해한다고 잘 알려진 curcumin 이외에, 다양한 플라보노이드 화합물이 질량 스펙트럼 DB 검색을 통하여 확인되었다. In vitro 연구 결과를 통하여 상기의 천연 추출물이 P-gp 활성을 저해하는 성분을 함유하고 있음을 확인하였다. 향후 이들 천연 추출물의 화학감작제 후보물질로의 사용 가능성에 대한 in vivo 연구가 필요할 것이다.

• 한국생물물리학회:학술대회논문집
• /
• 한국생물물리학회 2003년도 정기총회 및 학술발표회
• /
• pp.58-58
• /
• 2003

The envelope glycoprotein of HIV, gp41, mediates the membrane fusion with human cells. The extracellular domain of gp41 has two helical regions. The N-terminus helical region (N-helix) forms trimeric coiled coil, interacts with the C-terminus helical region (C-helix) of gp41 to form a stable helical bundle structure. In this study, we have shown that the N-helix of gp41 has membrane interacting and disrupting abilities. It was localized into the interface of the lipidic phase and head group of the membrane. In contrast, the N-helix region with membrane fusion defective mutations could not bind to membrane. In addition, the N-helix bound on the membrane was released from the membrane by the C-helix, and the complex of the N- and C-helix did not interact with membrane. These results suggested that the membrane binding ability of the N-helix is necessary for the fusion activity of gp41, and such property is possibly controlled by the C-helm.

• 통합자연과학논문집
• /
• 제6권4호
• /
• pp.205-210
• /
• 2013

Human P-gp is a protein responsible for the multidrug resistance (MDR) and causes failure of cancer chemotherapy. Till date no X-ray crystal structure is reported for this membrane protein, which hampers active research in the field. We performed homology modeling to develop three dimensional (3D) model of P-gp, and docking studies of the verapamil and curcumin have been performed to gain insight into the interaction mechanism between inhibitors and P-gp. It was identified that the inhibitors docked into the upper part of P-gp and interacted through the hydrophobic interactions.

• 한국동물학회:뉴스레터
• /
• 제12권2호
• /
• pp.120.1-120
• /
• 1995

No Abstract, See Full Text

• 한국동물학회:학술대회논문집
• /
• 한국동물학회 1995년도 한국생물과학협회 학술발표대회
• /
• pp.256.1-256
• /
• 1995

No Abstract, See Full Text

• 한국동물학회:학술대회논문집
• /
• 한국동물학회 1997년도 한국생물과학협회 학술발표대회
• /
• pp.285.1-285
• /
• 1997

No Abstract, See Full Text

• Journal of Pharmaceutical Investigation
• /
• 제37권3호
• /
• pp.131-135
• /
• 2007

A previous report recently demonstrated that ultrasound-induced hyperthermia (USHT:0.4 watts (W)/$cm^2$ at $41^{\circ}C$) could increase cellular uptake of P-glycoprotein (P-gp) substrates in P-gp expressing cancer cell lines. Since P-gp plays a major role in limiting drug permeability in the multi-drug resistant (MDR) cells, studies were conducted to elucidate the mechanism of USHT on cellular accumulation of P-gp and non-P-gp substrate in MDR cells. To accomplish this aim, we studied the effects of USHT on the accumulation of P-gp substrate, R123 and non-P-gp substrate, antipyrine in MDR cells. We demonstrated that USHT increased permeability of hydrophobic molecules (R123 and $[^{14}C]$-antipyrine). The enhanced permeability is reversible and size-dependent as USHT produces a much larger effect on cellular accumulation of $[^{14}C]$-antipyrine (MW 188) than that of R123 (MW 380.8). These results suggest that USHT could affect MDR cells more sensitive than BBMECs. Also, the present results point to the potential use of USHT to increase cellular uptake of P-gp recognized substrates, mainly anti-cancer agents into cancer cells.