• Toxicological Research
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• 제23권3호
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• pp.189-196
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• 2007

Cytochrome P450 (P450) enzymes are the major catalysts involved in the biotransformation of various drugs, pollutants, carcinogens, and many endogenous compounds. Most of chemical carcinogens are not active by themselves but they require metabolic activation. P450 isozymes playa pivotal role in the metabolic activation. The activation of arylamines and heterocyclic arylamines (HAAs) involves critical N-hydroxylation, usually by P450. CYP1A2 plays an important role in these reactions. Broad exposure to many of these compounds might cause carcinogenicity in animals and humans. On the other hand, P450s can be also involved in the bioactivation of other chemicals including alcohols, aflatoxin B1, acetaminophen, and trichloroethylene, both in humans and in experimental animals. Understanding the P450 metabolic activation of many chemicals is necessary to develop rational strategies for prevention of their toxicities in human health. An important part is the issues of extrapolation between species in predicting risks and variation of P450 enzyme activities in humans.

• 한국식품영양과학회지
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• 제24권6호
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• pp.859-866
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• 1995

본 연구에서는 액체식이로 알코올을 열량의 35%로 6주간 섭취시킨 흰주의 간조직내 지질과산화물과 glutathione 이용효소계의 활성도 및 cytochrome P-450에 미치는 영향을 살펴보고 아울러 간암의 발암원으로 알려진 2-AAF를 투여하여 이들의 상호효과를 조사한 결과 다음과 같은 결과를 얻었다. 1. 체중, 간무게, 그리고 체중에 대한 간무게의 알코올에 대한 효과는 유의적인 차이를 보여 체중은 알코올에 대한 효과는 유의적인 차이를 보여 체중은 알코올 섭취군이 유의적으로 감소하였고 간무게 및 체중에 대한 간무게는 알코올군의 유의적으로 증가하였다. 2. Microsome의 지질과산화물 함량 및 cytosol의 glutathione peroxidase, glutathione reductase 활성도는 알코올과 2-AAF 투여시 모두 유의적인 차이를 보이지 않았으나, cytosol의 glutathione S-transferase 활성도는 알코올과 2-AAF에 의해서 모두 유의적으로 증가하였고 알코올 섭추와 함께 투여시 GST 활성도가 가장 많이 증가하였다. 3. Microsome의 cytochrome P-450 및 cytochrome b5 함량에 대한 알코올 효과는 cytochrome P-450 함량을 증가시키는 경향이 있고 cytochrome b5는 유의적인 증가를 보여 주었으며 2-AAF 투여 역시 cytochrome P-450의 유의적인 증가를 유도하였다. 따라서 알코올 섭취와 2-AAF 함께 투여 시 cytochrome P-450의 함량이 대조군의 약 2.2배 정도 증가하였으며 cytochrome b5 함량이 1.7배로 높이 증가하였다. 이는 2-AAF가 cytochrome P-450을 유도하여 자신의 대사를 촉진시키며 알코올의 섭취 또한 2-AAF의 hydroxylation을 증가시킬 수 있는 것으로 생각된다. 이상의 결과에서 과량의 알코올을 만성적으로 섭취시 간조직내의 microsome의 MFO system에 영향을 미쳐서 발암물질의 생체 활성화를 촉진시킬 수 있고 또한 GST의 활성도를 증가시키므로 어느 정도 발암과정에 영향을 미치는 것으로 생각된다.

• Biomolecules & Therapeutics
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• 제30권1호
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• pp.1-18
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• 2022

Drug-drug interactions are a major cause of hospitalization and deaths related to drug use. A large fraction of these is due to inhibition of enzymes involved in drug metabolism and transport, particularly cytochrome P450 (P450) enzymes. Understanding basic mechanisms of enzyme inhibition is important, particularly in terms of reversibility and the use of the appropriate parameters. In addition to drug-drug interactions, issues have involved interactions of drugs with foods and natural products related to P450 enzymes. Predicting drug-drug interactions is a major effort in drug development in the pharmaceutical industry and regulatory agencies. With appropriate in vitro experiments, it is possible to stratify clinical drug-drug interaction studies. A better understanding of drug interactions and training of physicians and pharmacists has developed. Finally, some P450s have been the targets of drugs in some cancers and other disease states.

• 한국수의병리학회지
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• 제1권1호
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• pp.33-39
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• 1997

We investigated metabolism and carcinogenesis in livers of Sprague-Dawley rats fed juices and pelleted diets containing Korean native plants petasites japonicus Maxim by evaluating cell localization and expression of cytochrome P450s and GST-P. Anti-cytochrome P450s application in liver sections revealed three to four times increased expression of cytochrome P450E1 immunoreactivity in degenerative hepatocytes when compared to histologically normal hepatocytes. Anti-GST-P in showed positive pren plastic foci as well as in individual hepatocytes randomly scattered throughout all liver sections examined. Additionally GST-P was evident in proliferative endothelial cells and biliary epithelial cells in exposed rat livers. These results suggested that the increased level of cytochrome P4502E1 in affected hepatocytes was a direct consequence of Petasites japonicus toxicity. Further immunoreactivity to anti-GST-P in hepatocytes endothelial cells and biliary epithelial cells indicated a possible preneoplastic effects of Petasites japonicus in Sprague-Dawley rat.

• BMB Reports
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• 제37권5호
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• pp.629-633
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• 2004

NADPH-cytochrome P450 reductase (CPR) transfers electrons from NADPH to cytochrome P450, and catalyzes the one-electron reduction of many drugs and foreign compounds. Various forms of spectrophotometric titration have been performed to investigate the electron-accepting properties of CPR, particularly, to examine its ability to reduce cytochrome c and ferricyanide. In this study, the reduction of 1,1-diphenyl-2-picrylhydrazyl (DPPH) by CPR was assessed as a means of monitoring CPR activity. The principle advantage of DPPH is that its reduction can be assayed directly in the reaction medium by a continuous spectrophotometry. Thus, electrons released from NADPH by CPR were transferred to DPPH, and DPPH reduction was then followed spectrophotometrically by measuring $A_{520}$ reduction. Optimal assay concentrations of DPPH, CPR, potassium phosphate buffer, and NADPH were first established. DPPH reduction activity was found to depend upon the strength of the buffer used, which was optimal at 100 mM potassium phosphate and pH 7.6. The extinction coefficient of DPPH was $4.09\;mM^{-1}\;cm^{-1}$. DPPH reduction followed classical Michaelis-Menten kinetics ($K_m\;=\;28\;{\mu}M$, $K_{cat}\;=\;1690\;min^{-1}$). This method uses readily available materials, and has the additional advantages of being rapid and inexpensive.

• 동의생리병리학회지
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• 제22권1호
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• pp.155-161
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• 2008

Carbon tetrachloride $(CCl_4)-induced$ liver injury depends on a toxic agent that has to be metabolized by the liver NAPDH-cytochrome P450 enzyme system to a highly reactive intermediate. Although several isoforms of cytochrome P450 may metabolize $CC1_4$, attention has been focused largely on the cytochrome P450 2E1 (CYP2E1), which is ethanol-inducible. Alternations in the activity of CYP2E1 affect the susceptibility to hepatic injury from $CC1_4$. In this study, the liver protective effect of the hot water extracts of Scutellaria radix (SR) was investigated. The SR exhibited a hepatoprotective activity against $CCl_4-induced$ liver damage in Chang liver cells. The expression of CYP2E1, measured by RT-PCR and Western blot analysis, was significantly decreased by SR treatment in Chang cells. Based on these findings, it is suggested that hepatoprotective effect of SR possibly related to downregulation of CYP2E1 expression.

• Toxicological Research
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• 제14권3호
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• pp.293-300
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• 1998

Previous studies have shown that the heterocycles including thiazoles are efficacious in inducing phase phase II metabolizing enzyme as well as certain cytochrome P450s and that the inductin of these matabolizing enzymes by the heterocyclic agents is highly associated with their hepatotoxicity. In the present study, the effects of benzylisothiazole (BIT), which has a isothiazole moiety, on the expression of microsomal epoxide hydrolase (mEH), major glutathione S-transerases and cytochrome P450s were studied in the rat liver in association with its hepatotoxicity. Treatment of rats with BIT(1.17 mmol/kg, 1~3d) resulted in substantial increases in the mEH. rGSTA2, rGSTA2, rGSTM1 and rGSTM2 mRNA levels, whereas rGSTA3 and rGSTA5 mRNA levels were increased to much lesser extents. A time-course study showed that the mRNA levels of mEH and rGSTs were greater at 24hr after treatment than those after 3 days of consecutive treatment. Relative changes in mEH and rGST mRNA levels were consistent with those in the proteins, as assessed by Western immunoblot analysis. Hepatic cytochrom P450 levels were monitored after BIT treatment under the assumption that metabolic activation of BIT may affect expression of the enzymes in conjunction with hepatotoxicity. Immunoblot analysis revealed that cytochrome P450 2B1/2 were 3-to 4-fold induced in rats teatd with BIT(1.17 mmol/kg/day.3days), whereas P450 1A2, 2C11 and 3A1/2 levels were decreased to 20~30% of those in unteatd rats. P450 2E1 was only slightly decreased by BIT. Thus, the levels of several cytochrome P450s were suppressed by BIT treatment. Rats treated with BIT at the dose of 1.17mmol/kg for 3 days exhibited extensive multifocal nodular necrosis with moderate to extensive diffuse liver cell degeneration. No notable toxicity was observed in the kidney. These results showed that BIT induces mEH and rGSTs in the liver with increases in the mRNA levels, whereas the agent significantly decreased major cytochrome P450s. The changes in the detoxifying enzymes might be associated with the necrotic liver after consecutive treatment.

• 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.209.1-209.1
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• 2003

We have previously shown that 2, 3', 4, 5' -tetramethoxystilbene(TMS) from synthetic trans-stilbene analogues, is one of the most potently selective inhibitor of recombinant human cytochrome P450 1B1 in vitro. In the present studies. the effects of TMS on the expression of cytochrome P450 1B1 were investigated in human cancer cell lines such as MCF-7 and HL -60. TCDD-stimulated P450 1B1 protein and mRNA expression was significantly suppressed by TMS in a dose-dependent manner. (omitted)

• Biomolecules & Therapeutics
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• 제17권4호
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• pp.455-460
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• 2009

Foods of plant origin, especially fruits and vegetables, have attracted attention because of their potential benefits to human health. In this report, Rubi Fructus (RF), the dried unripe fruit of Rubus coreanus Miq (Rosaceae) and ellagic acid (EA) purified from RF were used to test their potential hepatoprotective effect against acetaminophen (AAP)-induced hepatotoxicity in rats. RF extract (RFext) and EA reduced the elevated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) in serum and the content of lipid peroxide in liver by AAP administration, while the increment of the cellular glutathione (GSH) content and the induction of glutathione S-transferase (GST) and glutathione peroxidase (GSH-PX) which were decreased by AAP administration. RFext and EA from RFext did not affect the two major form of cytochrome P450s, cytochrome P450 2E1 (CYP2E1) and cytochrome P450 1A2 (CYP1A2), but downregulated the cytochrome P450 3A4 (CYP3A4) related to the conversion of AAP to N-acetyl-P-benzoquinone imine (NAPQI). These results suggest that RFext and EA from RF exhibit a hepatoprotective effect not only by increasing antioxidant activities but also by down-regulating CYP3A4 in the AAP-intoxicated rat.

• Biomolecules & Therapeutics
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• 제3권4호
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• pp.245-250
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• 1995

The carbon tetrachloride($CCl_4$) has been demonstrated to have a hepatotoxic effect in human or many other species. To investigate the enzyme induction of mixed function oxygenases in liver of male Sprague-Dawley rats a single 0.1, 0.5 mι/kg dose of carbon tetrachloride were given. At 24 hr after a single dose of 0.1 mι CC1$_4$/kg weight, methanol extract of Hedera rhombea leaves was administered with 100, 500 mg/kg weight. Assays of 7-ethoxyresorufin-Ο-deethylation(EROD),7-benzyloxyresorufin-Ο-deathylation(BROD),4-nitro-phenol-UDP-glucuronosyltransferase(UDPGT), Western blot and RNA slot blot were used as representatives of the activities of cytochrome P-450 enzymes. The change of the activity of CYP1A1 form measured by EROD assay and Western analysis using 1-7-1 monoclonal antibody was not observed. The activity CYP2B1 form by BROD assay and using 2-66-3 monoclonal antibody was remarkably increased. Elevated level of CYP2B1 mRNA was shown by slot hybridization with 2B1-specific probe. Administration of methanol extract of Hedera rhombea leaves reversed the enzyme activity and the level of mRNA, which suggest the chemoprotective effect of methanol extracts of Hedera rhombea leaves to carbon tetrachloride hepatotoxlcity.