• 대한약리학회지
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• 제16권2호
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• pp.45-53
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• 1980

Lipid peroxidation in vitro has been identified as a basic deteriorative reaction in cellular mechanism of aging processes, such as air pollution oxidant damage to cell and to the lung, chlorinated hydrocarbon hepatotoxicity. Many experimental evidences were reported by several investigators that lipid peroxidation could be one of the principle causes for the hepatotoxicity produced by $CCl_4$. It is now reasonably established that $CCl_4$ is activated to a free radical in vivo, that lipid peroxidation occurs very quickly in microsomes prepared from damaged livers, that the peroxidation is associated with loss of enzyme activity of microsomes, and that various antioxidants can protect animals against the hepatotoxic effect of $CCl_4$. Recent studies have drawn attention to some other feature of microsomal lipid peroxidation. Incubation of liver microsomes in the presence of NADPH has led to a loss of cytochrome $P_{450}$. However, the presence of an antioxidant prevented lipid peroxidation and preserved cytochrome $P_{450}$. Decrease of cytochrome $P_{450}$ in microsomes under in vitro incubation can be enhanced by $CCl_4 and these changes were parallel to a loss of microsomal polyunsaturated fatty acid and formation of malonaldehyde. The primary purpose of this experiment was to study the effect of riboflavin tetrabutylate on lipid peroxidation, specially, the relationship between lipid peroxidation and drug metabolizing enzyme system which is located in smooth endoplasmic recticulum as well as the effect of ritoflavin tetrabutylate on drug metabolizing enzyme system of animal treated with $CCl_4$. Albino rats were used for experimental animal. In order to induce drug metabolizing enzyme system, phenobarbital was injected intraperitoneally. $CCl_$ and riboflavin tetrabutylate were given intraperitoneally as solution in olive oil. Microsomal fraction was isolated from liver of animals and TBA value as well as the activity of drug metabolizing enzyme were measured in the microsomal fractions. The results are summerized as following. 1) The secobarbital induced sleeping time of $CCl_4$ treated rat was about 2 times longer than that of the control group. However, the pretreatment with riboflavin tetrabutylate inhibited completely the lengthened sleeping time due to $CCl_4$ treatment. Furthermore TBA value was significantly increased in $CCl_4$ treated rat in comparison to control group tut the increase of TBA value was prevented by the pretreatment with riboflavin tetrabutylate. On the other hand, the activity of hepatic drug metabolizing enzyme was decreased in $CCl_4$ group, however, the pretreatment with riboflavin tetrabutylate also prevented the decrease of the enzyme activity caused by $CCl_4$. 2) The effect of riboflavin tetrabutylate on TBA value and the activity of drug metabolizing enzyme in vitro was similar to in vivo results. Incubation of liver microsome from rat in the presence of $CCl_4$, $Fe^{++}$, or ascorbic acid has led to the marked increase of TBA value, however, the addition of riboflavin tetrabutylate in incubation mixture prevented significantly the increase of TBA value, suggesting the inhibition of lipid peroxidation. In accordance with TBA value, the activity of drug metabolizing enzyme was inhibited in the presence of $CCl_4$, $Fe^{++}$, ascorbic acid but the addition of riboflavin tetrabutylate protected the loss of the enzyme activity in microsome under in vitro incubation.

• 사상체질의학회지
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• 제15권1호
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• pp.90-108
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• 2003

Osuyubujaijung-tang(OBT) and Sipyimiguanjung-tang(SGT) has been developed as prescriptions for the Soyeumin constitution. The hepatoprotective effect of the water extract of Osuyubujaijung-tang(OBT) and Sipyimiguanjung-tang(SGT) was investigated against carbon tetrachloride (CCl4)-induced hepatic damage. A single intra-peritoneal injection of CCl4 produced liver damage in rats as manifested by the significant rise of aspartate aminotransferase(AST), alanine aminotransferase(ALT), and alkaline phosphatase(ALP) in serum as compared to those of untreated normal group. Pretreatments of rats with Osuyubujaijung-tang(OBT) and Sipyimiguanjung-tang(SGT) 500 mg/kg for 7 days) were significantly reduced AST, ALT, and ALP levels compared with CCl4-treated control group. Treatment of rats with CCl4 led to significantly increase in lipid peroxidation and significantly decrease in cytochrome P450 and P450 reductase. The oral administration of Osuyubujaijung-tang(OBT) and Sipyimiguanjung-tang(SGT) water extract significantly inhibited the accumulation of microsomal thiobarbituric acid reactive substance (TBARS) and increased the cytochrome P450 and P450 reductase activity. All these biochemical alterations resulting from CCl4 administration were inhibited by the pretreatment with Osuyubujaijung-tang(OBT) and Sipyimiguanjung-tang(SG1) extract. These results suggest that Osuyubujaijung-tang(OBT) and Sipyimiguanjung-tang(SGT) water extract can be useful as a hepatoprotective agent. And the effect of NO modulation by NO synthesis or precursors, and Osuyubujaijung-tang(OBT) and Sipyimiguanjung-tang (SGT) water extract was researched on chronic liver damage induced by CCl4 administration. It was observed that endogenous NO protected the liver from lipid peroxidation, fibrosis, and damage. Osuyubujaijung-tang(OBT) and Sipyimiguanjung-tang(SGT) water extract showed the hepatoprotective effect on the chronic liver cirrhosis model and relationship with NO modulation.

• Toxicological Research
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• 제13권4호
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• pp.339-347
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• 1997

Disulfiram (DSF) and diethyldithiocarbamate (DDC), a reduced form of DSF, protect the liver against toxicant-induced injury through inhibition of cytochrome P450 2E1. The effect of DSF and DDC on the levels of major hepatic microsomal epoxide hydrolase (mEH) and glutathione S-transferase (GST) expression was comparatively studied, given the view that these enzymes are involved in terminal detoxification events for high energy intermediates of xenobiotics. Treatment of rats with a single dose of DSF (20-200 mg/kg, po) resulted in 2- to 15-fold increases in the mEH mRNA level at 24 hr with the ED$_{50}$ value being noted as 60 mg/kg. The mEH mRNA level was elevated ~15-fold at 24 hr after treatment at the dose of 100 mg/kg, whereas the hepatic mRNA level was rather decreased from the maximum at the dose of 200 mg/kg, indicating that DSF might cause cytotoxicity at the dose. In contrast to the effect of DSF, DDC only minimally elevated the mEH mRNA level at the doses employed. DSF moderately increased the major GST mRNA levels in the liver as a function of dose, resulting in rGSTA2, rGSTA3/5 or rGSTM1 mRNA levels being elevated 3- to 4-fold at 24 hr post-treatment, whereas the rGSTM2 mRNA level was not altered. DDC, however, failed to stimulate the mRNA levels for major GST subunits, indicating that the reduced form of DSF was ineffective in stimulating the GST the expression. The effect of other organosulfides including aldrithiol, 2, 2'-dithiobis(benzothiazole) (DTB), tetramethylthiouram disulfide (TMTD) and allyl disulfide (ADS) on the hepatic mEH and GST mRNA expression was assessed in rats in order to further confirm the increase in the gene expression by other disulfides. Treatment of rats with aldrithiol (100 mg/kg, po) resulted in a 16-fold increase in the mEH mRNA level at 24 hr post-treatment. DTB, TMTD and ADS also caused 5-, 9- and 12-fold increases in the rnRNA level, respectively, as compared to control. Thus, all of the disulfides examined were active in stimulating the mEH gene in the liver. The organosulfides significantly increased the rGSTA2, rGSTA3, rGSTA5 and rGSTM1 mRNA levels at 24 hr after administration. In particular, aldrithiol was very efficient in stimulating the rGSTA and rGSTM genes among the disulfides examined. These results provide evidence that DSF and other sulfides effectively stimulate the mEH and major GST gene expression at early times in the liver and that DDC, a reduced form of DSF, was ineffective in stimulating the expression of the genes, supporting the conclusion that reduced form(s) of organosulfur compound(s) might be less effective in inducing the mEH and GST genes through the antioxidant responsive element(s).

• 약학회지
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• 제52권4호
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• pp.316-321
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• 2008

The hepatoprotection by the methanol extract of Oenanthe javanica DC (water dropwort) (OJME) was investigated in Sprague Dawley rats with inducing liver damage by acetaminophen. After OJME administration for 1 week, the increase of hepatic lipid peroxide level by acetaminophen-induced hepatotoxicity was significantly reduced. In case of phase I microsomal enzyme systems including cytochrome P-450, aminopyrine N-demethylase and aniline hydroxylase, any significant differences between in control and in OJME-pretreated group was observed after acetaminophen treatment. However, the pretreatment of OJME maintained the hepatic glutathione level and the activity of liver cytosolic glutathione S-transferase, which was significantly decreased by the acetaminophen intoxication. Among the glutathione-generating system, glutathione reductase was more responsible for its biosynthesis rather than ${\gamma}-glutamylcystein$ synthetase. OJME itself showed the strong inhibition activity on DPPH radical generation. In conclusion, OJME administration maintains the liver glutathione pool and hepatic glutathione S-transferase activity, in addition with its high anti-oxidative capability, to show hepatoprotective effect from acetaminophen intoxication.

• 한국식품영양과학회지
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• 제26권4호
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• pp.675-681
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• 1997

체내에서 영양소의 흡수에 영향을 미치는 에탄올과 섬유소 및 단백질의 급여수준에 따른 이 들 상호작용을 구명하기 위해 에탄올을 투여한 횐쥐에게 단백질 급여 수준을 7%와 20%로 달리 하고 섬유소를 5%와 10% 첨가한 실험식이를 5주간 급여하므로써 이들 영양소가 에탄을 대사효소와 항산화 물질에 미치는 영향을 관찰하였다. Aldehyde dehydrogenase(ADH)와 microsomal ethanol oxidizing system(MEOS) 활성은 에탄을 투여시 대조군에 비해 유의적으로 증가하였으며, 특히 MEOS 활성은 단백질 정상 급여와 정상섬유소 급여시 그 증가가 현저하였다. 에탄을 투여로 감소된 aldehyde de-hydrogenase(AIDH) 활성은 정상섬유소군의 경우 단백질 적정 급여시 유의적인 감소를 나타내었다. Cytoch-rome P-450(P-450) 활성은 에탄을 투여로 증가되었으며 에탄을 투여군에서 단백질 정상급여와 과량의 섬유소 급여로 유의하게 감소되었다. Xanthine oxidase (XO) 활성은 에탄을 투여로 증가하는 경향이었으며, 저 단백군에 비하여 단백질 적정 급여시 유의적인 증가를 나타내었다. 또한 섬유소 급여수준에 따른 XO 활성은 에탄올 투여군 중 단백질 정상군에서만 유의적인 차이가 관찰되었다. 에탄을 투여는 간조직 중의 글루타티온 함량을 유의적으로 감소시켰으며, 단백질 결핍에 따른 영향이 현저하게 나타났다. 간조직 중의 지질과 산화 함량은 단백질 결핍시 에탄올 투여로 증가하였다. 이상의 결과에서 에탄올을 해독키 위하여 간의 ADH와 MEOS 활성이 증가되었으며 이로 인해 생성된 아세트알데히드는 AIDH 보다 XO를 통해 해독된 것으로 나타났다. 또한 에탄올 대사효소 활성에 요구되는 단백질 공급과 10% 즉, 과량의 섬유소 급여 보다 5% 섬유소 급여시 에탄올성 간손상을 경감시킬 수 있을 것으로 사료된다.

• Environmental Analysis Health and Toxicology
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• 제6권3_4호
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• pp.105-121
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• 1991

The object of this study is to investigate the toxicity of fenvalerate [(RS)-$\alpha$-cyano-3 -phonoxybenzyl-(RS)-2-(4-ch1orophenyl)-3-methylbutyrate] and the effect of carbaryl on the toxicity of fenvalerate. Rats were treated with fenvalerate (50 mg/kg, 100 mg/kg), carbaryl (50 mg/kg, 100 mg/kg) or mixtures of the two compounds (fenvalerate+carbaryl: 50 mg/kg+50 mg/kg, 50 mg/kg+100 mg/kg) by oral administration for 1~3 weeks. Control groups were treated with corn oil. The experimental results were summarized as follows. 1. LD$_{50}$ values of fenvalerate and carbaryl in male rats were 385 mg/kg and 625 mg/kg respectively. When 50 mg/kg and 100 mg/kg of carbaryl were administratrd, LD$_{50}$values of fenvalerate were 265 mg/kg and 225 mg/kg respectively. 2. Biochemical parameters such as ALT, LDH and glucose in serum were much more increased in the groups treated with mixture than the groups treated with either one of fenvalerate or carbaryl. 3. The groups treated with carbaryl and mixture for 3 weeks, the contents of cytochrome P-450 in the liver were significantly increased. In renal microsomal fractions, however, no significant changes of drug metabolizing enzyme activities were observed. 4. The activities of aniline hydroxylase in hepatic microsomal fractions were increased in the groups treated with fenvalerate and mixture and activity was much more increased in the groups treated with mixture. 5. The activities of ATPase in the groups treated with fenvalerate were decreased than that of groups treated with mixture. TBA values and the activity of glucose-6 -phosphatase in the liver were not significantly changed. 6. In mixture treated groups, the activities of cholinesterase in serum and in the liver were more decreased than those of carbaryl treated groups. The activities of carboxylesterase in serum in the liver were slightly increased in mixture treated groups, but in fenvalerate treated groups, the activities of carboxylesterase were much more increased than those of control groups. 7. As a result of this study, when carbaryl was as the synergist of fenvalerate, carbaryl inhibited the activities of esterases, so the toxicity of fenvalerate was increased.sed.

• 생약학회지
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• 제36권2호통권141호
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• pp.81-87
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• 2005

The effects of the DWP-04 [DDB:selenium yeast:glutathione (31.1 : 6.8 : 62.1 (w/w%)] on acetaminophen detoxification enzyme system were studied in rats. Treatment with DWP-04 was prevented againt acetaminophen-induiced hepatotoxicity in rat as evidenced by the decreased formation of lipid peroxide. Effect of DWP-04 on the activities of free radical-generating enzymes, free radical scavenging enzymes and glutathione-related enzymes as well as detoxification mechanism of DWP-04 against acetaminophen-treated was investigated in rat. Activities of cytochrome p450, cytochrome b5, aminopyrine demethylase and aniline hydroxylase as free radical-generating enzymes activities were decreased by the treatment with DWP-04 against acetaminophen treated. Although acetaminophen-induced hepatotoxicity results in the significantly decrease in the level of hepatic glutathione and activities of glutathine S-transferase, quinone reductase, glutathione reductase and ${\gamma}-glutamyl-$cysteine synthetase, these decreasing effects were markedly lowered in the DWP-04-treated rat. Therefore, it was concluded that the mechanism for the observed preventive effect of DWP-04 against the acetaminophen-induced hepatotoxicity was associated with the decreased activities in the free radical-generating enzyme system.

• 대한의생명과학회지
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• 제9권2호
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• pp.75-84
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• 2003

To evaluate the influence of hepatic oxygen free radical systems on liver injury by topical p-phenylenediamine (PPD) application on rat skin, PPD (25 mg/16.5 $\textrm{cm}^2$) was topically applied to the abdominal region 5 times every other day and sacrificed. By PPD treatment, increasing rate of liver weight/body weight (%), serum activities of alanine aminotransferase and aspartate aminotransferase and decreasing rate of microsomal glucose-6-phosphatase activity were higher in the rats fed tungstate supplemented diet than those fed a standard diet. These findings indicate that group fed tungstate supplemented diet have more severe liver injury compared with group fed standard diet on topical PPD application. However, the activities of oxygen free radical generating enzymes such as xanthine oxidase (XO) and cytochrome P450 dependent aniline hydroxylase and those of oxygen free radical scavenging enzymes were not found to be different between these two animal groups. In the present study, a novel monitoring method to detect the generating of oxygen free radicals in liver extract was devised. Throughout this method, the oxidized PPD produced by oxygen free radicals was determined colorimetrically. The increasing rate of PPD oxidation by liver homogenate was higher in tungstate fed animals than in standard diet fed ones. Among the fractionations of liver extract, the mitochondrial and postmitochondrial fractions in the liver extract of tungstate fed animals led to a higher availability of PPD oxidation by PPD treatment compared with standard diet fed ones. In conclusion, these results suggest that an enhanced liver injury in tungstate fed animals treated with PPD may be due to oxygen free radicals produced in other systems except oxygen free radicals generating from cytosolic XO system. Especially, oxidative availability by PPD can be used for oxygen free radical detection in some tissue.

• Tuberculosis and Respiratory Diseases
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• 제45권3호
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• pp.546-552
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• 1998

연구배경: Macrolide란 구조식에 14-number macrocyclic lactone ring을 갖는 항생제를 총칭한다. 최근 개발된 clarythromycin, azythromycin, roxithromycin 등은 기존의 erythromycin에 비하여 소화관 흡수가 용이하고, 반감기가 길며, 위장관 부작용은 덜하면서 몇몇 세균속에 대해서는 더욱 강력한 항균 효과가 있다고 알려져 있다. Erythromycin은 간장의 cytochrome P-450 효소계에 의해 불활성화 되기 때문에, 특히 호흡기 질환 환자에서 사용되는 theophylline의 혈중농도를 증가시켜 theophylline toxicity를 초래할 수 있다고 알려져 있다. 그러나 현재까지 new macrolide에 있어서는 이러한 효과에 대해서는 임상 연구가 미미한 실정이다. 방 법: 기관지 천식환자에서 erythromycin (1000mg/day), clarithromycin(500mg/day), azithromycin(500mg/day), roxithromycin(300mg/day) 등을 theophylline(400mg/day)과 경구 복합 투여하여, 투여전, 투여 후 1주 및 4주(azythyromycin은 1주)에 각각 theophylline 혈중 농도와 청소율을 측정하여 혈중 theophylline 농도 및 청소율에 대한 erythromycin과 new macrolides 항생제의 영향을 평가하고자 하였다. 결 과: Erythromycin과 roxithromycin 투여군에서는 투여 1주 후부터 유의한 theophylline 혈중농도의 상승을 보였으며 특히, erythromycin 투여군에서는 2예에서 병합 투여를 중지하였다. 이러한 소견은 theophylline 청소율에서도 유사하였으나 1주 및 4주간에는 유의한 상승소견을 보이지 않았다. Clarithromycin, azithromycin 투여군에서는 병합 투여중 유의한 혈중 농도의 상승이나 청소율의 감소 소견은 관찰되지 않았다. 결 론: 이상의 결과로 erythromycin 혹은 roxithromycin 투여 환자에 대하여 theophylline을 동시에 복합 투여하는 경우 혈중 theophylline 농도가 예상보다 증가될 수 있으므로 적절한 주기적 관리가 요할 것으로 사료된다.

• 한국식품영양과학회지
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• 제29권5호
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• pp.935-942
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• 2000

갈화(flower of Pueraria lobata) 분획 및 활성 성분의 급여가 아급성 알코올 중독된 흰쥐에서의 해독에 미치는 영향을 연구할 목적으로, 25% alcohol을 6주간 투여하여 아급성 알코올 중독상태를 유발한 흰쥐를 3주 더 사육하면서 혈액중 지질 함량의 변동, 알코올 대사계 효소의 활성을 비교 검퇀 결과는 다음과 같다. 알코올 단독 급여군은 대조군에 비하여 체중이 감소되었으며, 알코올-갈화 tectorigenin 급여군의 체중증가량은 대조군 수준에는 미치지 못하였으나, 알코올 단독 급여군보다는 유의적인 회복을 나타냈다. 알코올 단독 급여군의 총지방, 중성 지방, 인지질 함량이 대조군에 비하여 중가하엿고, 알코올-갈화 tcctorigcnin 급여군과 알코올-갈화 kaikasapomin III 급여군의 총지방, 주성지방 함량은 대조군 수준에는 미치지 못하였으나, 알코올 단독 급여군에 비하여 유의적으로 회복되었다. 알코올 단독 급여군의 total cholesterol, LDL-cholesterol, VLDL-cholesterol 함량, AI는 대조군에 비하여 증가하였고, 알코올-갈화 tectorigcnin, kaikasaponin III 급여군은 대조군 수준에는 미치지 못했으나, 알코올 단독 급여군에 버해 유의적으로 회복되았다. 알코올 단독 급여군의 HDL-cholcsterol의 함량은 대조군에 비하여 감소하던 것이 알코올-갈화 tectorigenin 급여군과 알코올-갈화 kaikasaponin III 급여군에서는 대조군 수준에서는 미치지 못하나, 알코올 단독 급여군에 비하여 증가하였다. 알코올 급여 시 cytochrome P 450, AH와 AD활성은 대조군에 비하여 증가했으나, 알코올-갈화 tectorigenin 급여군과 알코올-갈화 kaikasaponin III 급여군의 경우 알코올 단독 급여군보다 낮게 나타났다. 알코올 급여시 ADH활성이 증가하였으며 알코올-갈화 tectorigenin 급여군과 알코올-갈화 kaikasponin III 급여군은 알코올 단독 급여군보다 높게 나타났다. MEOS의 활성은 알코올 급여 시 대조군에 비하여 중가를 보였고, 알코올-갈화 tectorigenin 급여군에서는 알코올 단독 급여군보다 유의적인 증가를 나타냈다. Catalase의 활성은 각 군간의 유의적인 차이를 볼 수 없었다. ALDH의 활성은 알코올 단독 급여군은 대조군의 활성에 비하여 감소되었으나, 알코올-갈화 tectorigenin 급여군과 알코올-갈화 kaikasaponin III 급여군에서 알코올 단독 급여군보다 유의적인 활성증가를 보였다. 이상의 결과를 종합해 볼 때 갈화로부터 분리된 tectorigenin과 kaikasaponin III는 아급성 알코올 중독된 흰쥐 간의 free radical 생성계 효소를 억제시켜 알코올로 인한 간손상을 회복시키고, 알코올 대사 효소계에 관여하여 해독작용에 영향을 미침으로써 알코올 해독에 도움을 줄 수 있을 것으로 사료된다.