• Archives of Pharmacal Research
• /
• 제27권2호
• /
• pp.199-205
• /
• 2004

Cytochrome P450 (P450) 1 enzymes such as P450 1A1, 1A2, and 181 are known to be involved in the oxidative metabolism of various procarcinogens and are regarded as important target enzymes for cancer chemoprevention. Previously, several hydroxystilbene compounds were reported to inhibit P450 1 enzymes and were rated as candidate chemopreventive agents. In this study, we investigated the inhibitory effect of 2-[2-(3,5-dimethoxyphenyl)vinyl]-thiophene (DMPVT), produced from the chemical modification of oxyresveratrol, on the activities of P450 1 enzymes. The inhibitory potential by DMPVT on the P450 1 enzyme activity was evaluated with the Escherichia coli membranes of the recombinant human cytochrome P450 1A1, 1A2, or 1B1 coexpressed with human NADPH-P450 reductase. DMPVT significantly inhibited ethoxyresorufin O-deethylation (EROD) activities with $IC_{50}$ values of 61, 11, and 2 nM for 1A1, 1A2, and 1B1, respectively. The EROO activity in OMBA-treated rat lung microsomes was also significantly inhibited by OMPVT in a dose-dependent manner. The modes of inhibition by DMPVT were non-competitive for all three P450 enzymes. The inhibition of P450 1B1-mediated EROD activity by OMPVT did not show the irreversible mechanism-based effect. The loss of EROD activity in P450 1B1 with OMPVT incubation was not blocked by treatment with the trapping agents such as glutathione, N-acetylcysteine, or dithiothreitol. Taken together, the results suggested DMPVT to be a strong noncompetitive inhibitor of human P450 1 enzymes that should be considered as a good candidate for a cancer chemopreventive agent in humans.

• 대한약리학회지
• /
• 제18권1호
• /
• pp.65-72
• /
• 1982

It has been known that retinoids are intrinsically of critical importance for control of premalignant epithelial cell differentiation. In the absence of retinoids, normal cellular differentiation and growth does not occur in epithelia such as those of trachea and bronchi. Furthermore, it was also reported that retinoid deficiency enhanced susceptibility to chemical carcinogenesis in the respiratory system, in the bladder, and in the colon of the experimental animal. In 1974, Bollag examined the effects of synthetic retinoids in prevention of development of cancer and demonstrated synthetic retinoids to have more favorable therapeutic index than retinoic acid for causing regression of skin papilloma in mice. Therefore, it was assumed that this anticarcinogenic effect of vitamin A derivatives could be due to modification of the metabolism of the carcinogenic polycyclic hydrocarbon, which must first be activated to exert their effect. Hill and Shih reported that vitamin A compounds and analogs had inhibitory effect on drug metabolizing enzyme from liver and lung tissue of mouse and hamster. Lucy suggested that the chemoprevention effect of vitamin A derivatives is due to reaction with molecular oxygen, and it is possible that inhibition of hydroxybenzpyrene formation is a result of this property. On the other hand, butylated hydroxytoluene which is a potent antioxidant strongly inhibited the formation of mammary tumor induced by dimethylbenranthracene. Also, it was observed that this antioxidant inhibited cancer induction in rats by N-2-fluo-renylacetamide. The purpose of this experiment was to investigate the effect of vitamin A derivatives such as retinoic acid and retinoid on drug-metabolizing enzyme and to determine whether riboflavin tetrabutylate or vitamin E could prevent of modify any changes induced by vitamin A delivatives in the rats. The results obtained were as followings. 1) Body weight was significantly reduced by retinoic acid, but not by retinoid. 2) Retinoic acid markedly increased liver weight while retincid showed no effect on liver weight. Treatment of riboflavin tetrabutylate did not affect retinoic acid-induced change in both body weight and liver weight. 3) Both retinoic acid and retinoid remarkably decreased the activity of aminopyrine demethylase. Pretreatment of riboflavin tetrabutylate, however, prevented inhibitory effect of retinoic acid on the enzyme activity. 4) No significant effect of vitamin E on aminopyrine demethylase was observed in both groups treated with retinoic acid and retinoid.

• 생명과학회지
• /
• 제23권10호
• /
• pp.1209-1215
• /
• 2013

그래핀(graphene)은 원자 하나의 두께를 가지는 흑연(graphite)의 단층으로서 탄소구조체들 중 하나이다. 그래핀은 최근 의학분야에서 광열요법을 이용한 암 발생의 예방효과와 DNA의 산화에 대한 보효효과를 가진다고 밝혀진 바 있다. 본 연구에서는 사람 섬유아육종세포(HT1080)에서 산화 스트레스와 MMPs에 대한 그래핀의 효과가 조사되었다. 항산화 효과에 대한 연구에서 그래핀은 DNA 산화에 대한 억제효과를 특이하게 나타내었으나 다른 산화 스트레스는 억제하지 않았다. 뿐만 아니라 그래핀은 세포 내 과산화수소를 생성시키는 phenazinemethosulfate(PMS)에 의하여 자극된 MMP-2 및 MMP-9의 발현과 활성을 감소시켰다. 특히 superoxide dismutase(SOD-2)와 같은 항산화 효소의 발현이 HT1080세포에서 감소하였는데, 이것이 시사하는 바는 SOD 발현수준의 감소가 그래핀의 항산화 효과로부터 기인 되었다는 것을 나타낸다. 이상의 결과로 그래핀의 존재에서 산화스트레스의 억제효과가 HT1080 세포에서 MMP-9의 활성과 발현을 감소시킬 수 있다는 것을 암시하고 있다. 이러한 연구 결과를 바탕으로 그래핀은 암 전이와 관련 있는 MMP-2 및 MMP-9의 활성과 발현의 억제를 통하여 암 억제에 도움을 줄 수 있어, 산업화를 위한 하나의 우수한 생의학 응용소재로 이용될 수 있으리라 기대된다.

• 생물환경조절학회지
• /
• 제18권4호
• /
• pp.448-453
• /
• 2009

본 연구에서는 참외 추출물의 항암활성에 대해 알아보기 위해 참외를 부위별로 나누어 quinone reductase 유도활성과 다양한 간암세포에서의 증식 억제활성을 조사하였다. 참외 꼭지와 참외 줄기 잎 부위에서 농도의존적으로 QR 유도활성이 증가하였고, $200{\mu}g/mL$ 농도에서는 각각 3.9, 1.5배의 유도활성을 나타내었다. 암세포 사멸 활성 측정법을 통한 항암활성 평가 실험에서 마우스 유래의 간암세포인 Hepa1c1c7 세포에 대해서 조사한 결과 꼭지와 줄기 잎 부위에서 높은 암세포 독성을 보였다. 이러한 결과를 기초로 인체유래의 암세포에 대한 항암활성을 평가하기 위해 인체유래 간암 세포주인 HepG2에 대한 세포 증식 억제활성을 농도별로 조사하였다. 꼭지와 줄기 잎 부위 모두 인체유래 간암 세포에 대해 증식 억제효과를 보여주었지만, 특히 꼭지 부위는 최고농도에서 60.3%의 높은 증식 억제효과를 보였다. 그러나 마우스 유래의 간암세포에 대한 활성보다 인체유래 간암세포에 대한 활성이 낮게 나타났다. 참외의 꼭지 추출물에서 QR 유도활성과 항암활성을 확인함으로써 향후 참외 비가식 부위의 기능성 소재로의 이용화에 대한 연구가 필요할 것으로 생각된다.

• Food Science and Biotechnology
• /
• 제17권2호
• /
• pp.367-372
• /
• 2008

Cellular protection against carcinogens could be achieved by the induction of phase 2 detoxifying and antioxidant enzymes such as glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO1). Nuclear transcription factor E2-related factor 2 (Nrf2) binds to antioxidant response element (ARE) in the promoter region of these genes and the resulting transactivation occurs. In the present study the effect of gujeolcho (Chrysanthemum zawadskii) roots on the Nrf2-ARE pathway were investigated. C. zawadskii root extract was fractionated with a series of organic solvents and their ability to induce Nrf2-ARE pathway was examined. We separated the most potent dichloromethane (DCM) fraction into 12 sub-fractions and found several sub-fractions with strong effects on the Nrf2-ARE pathway. Fraction 4 strongly induced the ARE-reporter gene activity as well as Nrf2 expression. Sitosterol was isolated as a major compound in fraction 4 although its activity was not as potent as its mother fraction. These results indicate that C. zawadskii roots might be used as a potential natural chemopreventive source.

• 한국식품위생안전성학회지
• /
• 제28권1호
• /
• pp.41-44
• /
• 2013

비록 천연유래물질 중의 하나인 통초가 항산화작용, 항염증작용 및 해열작용과 같은 효능이 있다고 알려져있지만, 종양에서의 암예방효능에 대한 연구는 보고된 바가 없다. 본 연구에서는 사람 자궁경부암세포주인 HEP-2세포에서 통초메탄올추출물의 증식억제 효능 및 관련 분자표적을 확인하고자 하였다. 통초메탄올추출물은 세포증식을 유의성있게 억제하고, 세포사멸을 유도하는 것으로 나타났다. 또한, Bid의 발현에 영향을 주어 truncation을 유도하고, 이로 인해 cytochrome c가 마이토콘드리아에서 세포질로 이동하도록 유도하였지만, Bid 이외의 다른 Bcl-2 family에는 영향을 주지 못했다. 따라서, 이러한 결과를 종합해 볼 때, 통초메탄올추출물은 자궁경부암에서 암예방효능을 가진 잠재성있는 천연추출물이 될 수 있을 것으로 사료된다.

• 동의생리병리학회지
• /
• 제17권6호
• /
• pp.1448-1452
• /
• 2003

The water extract of Scutellariae radix was treated to rat and the primary culture of hepatocytes, and the expressions of several glutathione S-transferase (GST) isozymes and the activity of GST Yc1/2 were investigated by Western blot and by the use of HPLC. The results were obtained as follows: The water extract of Scutellariae radix did not induce the expressions of cytosolic GST Ya and GST Yp in rat livers. But, the extract increased the expression of cytosolic GST Yc1/2 to 2-4 fold higher than control. The expression of GST Yc1/2 in the primary culture of rat hepatocytes was induced by the water extract of Scutellariae radix in a dose-dependent manner, reaching 21-fold over control with 50 ㎍/㎖ treatment. The induction of the expression of GST Yc1/2 in rat livers increased the formation of AFB₁-glutathione conjugate from AFB₁-8,9-epoxide which was made in the metabolism of AFB₁.

• BMB Reports
• /
• 제30권1호
• /
• pp.73-79
• /
• 1997

This study was designed to investigate the effects of dietary garlic powder on cytochrome P450 enzymes and membrane stability in murine hepatocarcinogenesis initiated by diethylnitrosamine (DEN). Male Sprague-Dawley rats received a single intraperitoneal injection of DEN (200 mg/kg body wt) dissolved in saline. After 2 weeks on a basal diet, animals were fed diets containing 0. 0.5. 2.0. or 5.0% garlic powder for 6 weeks, and were subjected to two-thirds partial hepatectomy. The areas of placental glutathione S-transferase (GST-P) positive foci were inhibited in rats fed with garlic diets. GST-P is the most effective marker for DEN-initiated lesions. Hepatic microsomal lipid peroxidation was significantly decreased in rats fed with 2.0 and 5.0% garlic powder diets compared with that observed in the control animals and hepatic microsomal glucose 6-phosphatase (G6Pase) activity was found to increase significantly in rats fed 0.5 and 2.0% garlic powder diets. Thus as little as 0.5% garlic powder has a positive effect on the stability of hepatic microsomal membranes. p-Nitrophenol hydroxylase (PNPH) activity and the level of cytochrome P450 2E1 protein in the hepatic microsomes from rats fed diets containing 2.0 and 5.0% garlic powder were much lower than those of control microsomes. Rats fed 5.0% garlic powder diets exhibited the lowest P450 2E1 activity and protein levels among groups. Pentoxyresorufin O-dealkylase activity and immunoblot (cytochrome P450 2B1) analyses were not different between groups. However, the levels of cytochrome P450 1A1/2 protein in rats fed 0.5 and 2.0% garlic powder were significantly induced compared to controls. These results suggest that 2.0% garlic powder is effective in inhibiting the areas of GST-P positive foci, modulating certain isoforms of cytochrome P450 enzymes and stabilizing the hepatic microsomal membrane. Thus, the selective modification of cytochrome P450 enzymes and membrane stability by dietary garlic powder may influence areas of GST-P positive foci and chemoprevention of post-initiation of rat hepatocarcinogenesis.

• Toxicological Research
• /
• 제17권
• /
• pp.251-256
• /
• 2001

The expression of phase II detoxifying enzymes is affected by a variety of compounds and the induction of the enzymes plays an essential role in chemoprevention. A variety of phytochemicals such as sulfur-containing chemoprotective agents (SCC) may trigger cellular signals and activate phase II gene expression through ARE activation. see induces glutathione S-transferases. Studies were conducted to investigate the role of mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI3-kinase) in the induction of GST (e.g. rGSTA2) by sec. We also studied the MAP kinase pathway responsible for the GST expression by see and compared that with the pathway activated by oxidative stress as a result of sulfur amino acids deprivation (SAAD). see inhibited phosphorylation of ERK1/2 although the effect of see on JNK and p38 MAP kinase was minimal. Wortmannin and LY294002. PI3-kinase inhibitors. abolished the increases in rGSTA2 mRNA and protein levels by SCC. Deprivation of cystine and methionine caused oxidative stress in H4IIE cells. as evidenced by a decrease in the reduced glutathione and an increase in prooxidant production. Electrophoretic mobility shift assay revealed that the ARE complex consisting of Nrf-1/2 and Maf proteins was activated 12~48 h. The rGSTA2 mRNA and protein levels were increased by SAAD. Activation of ARE and induction of rGSTA2 were both completely inhibited by PI3-kinase inhibitors. Inhibition of p38 MAP kinase by SB203580 prevented the ARE-mediated rGSTA2 induction. The results of this study showed that PI3-kinase might play an essential role in the ARE-mediated rGSTA2 induction by see or SAAD and that the dual MAP kinase pathways were responsible for the enzyme induction.

• Nutritional Sciences
• /
• 제7권2호
• /
• pp.76-82
• /
• 2004

Pine needles are known as a traditional medicine and their ingestion has been shown to be beneficial to human beings. Following induction of the neoplastic process in rats by azoxymethane (AOM), we determined the effects of pine needle supplementation on colon carcinogenesis and on antioxidant systems in the blood and liver. Five week old male Fisher 344 rats were injected with AOM (15 mg/kg) once a week for two weeks. After the second injection, 18 rats were randomly assigned into two groups and were fed a casein-based high-fat diet (120 g fat and 1 g cholesterol/kg diet) with or without pine needle powder (10%w/w). After 6 weeks, rats receiving pine needle powder showed a 40% lower incidence of the number of colonic preneoplastic lesions (aberrant crypts) and a 52% lower incidence of aberrant crypt foci (p<0.01). A significantly elevated level of erythrocyte catalase activity was observed in the pine needle supplemented group (17.4$\pm$1.1 vs. 24.5$\pm$1.5, p<0.01). Pine needle supplementation also increased liver glutathione peroxidase activity (7.5$\pm$0.6 vs. 14.6$\pm$0.6, p<0.01). Other antioxidant parameters such as erythrocyte glutathione peroxidase, liver catalase activity, and plasma total antioxidant potential (TRAP), showed no statistical differences between the two groups. Our data demonstrate that pine needle supplementation improves the antioxidant system and suppresses the formation of colonic preneoplastic lesions in AOM-treated rats. This result provides additional insights into the chemo-preventative properties of pine needles.