• Title, Summary, Keyword: drug metabolizing function

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Effects of Vitamins C and E on Hepatic Drug Metabolizing Function in Nypoxia/Reoxygenation (저산소 및 산소재도입시 vitamin C와 E가 간장 약물대사 기능에 미치는 영향)

  • 윤기욱;이상호;이선미
    • YAKHAK HOEJI
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    • v.44 no.3
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    • pp.237-244
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    • 2000
  • Liver isolated from 18 hours fasted rats was subjected to $N_2$hypoxia (for 45 min) followed by reoxygenation (for 30 min). The perfusion medium used was Krebs-Henseleit bicarbonate buffer (pH 7.4, $37^{\circ}C$). Vitamin C (0.5 mM) and trolox C (0.5 mM), soluble vitamin E analog, were added to perfusate. Lactate dehydrogenase (LDH), total glutathione, oxidized glutathione, lipid peroxide and drug-metabolizing enzymes were measured. After hypoxia LDH significantly increased but this increase was attenuated by vitamin C and combination of vitamin C and E. Total glutathione and oxidized glutathione in perfusate markedly increased during hypoxia and this increase was inhibited by vitamins C, E and its combination. Similarly; oxidized glutathione and lipid peroxide in liver tissue increased after hypoxia and reoxygenation and this increase was inhibited by vitamin I and combination of vitamin C and E. Hepatic drug metabolizing function (phase I, II) were suppressed during hypoxia but improved during reoxygenation. While vitamins C and E only increased glucuronidation, the combination of vitamin C and E increased the oxidation, glucuronidation and sulfation. Our findings suggest that vitamins C and E synergistically ameliorates hepatocellular damage as indicated by abnormalities in drug metabolizing function during hypoxia/reoxygenation and that this protection is in major part, caused by decreased oxidative stress.

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Alteration of Hepatic Drug Metabolizing Function after Traumatic Injury

  • Lee, Woo-Yong;Lee, Sang-Ho;Lee, Sun-Mee
    • Proceedings of the PSK Conference
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    • pp.301.1-301
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    • 2002
  • The aim of present study was to investigate effects of blunt trauma on alterations in cytochrome P-450 (CYP)-dependent drug metabolizing function and to determine the role of Kupffer cells in the hepatocellular dysfunction Rats underwent closed femur fracture (FFx) with associated soft-tissue injury under anesthesia. Control animals received only anesthesia. To deplete Kupffer cells in vivo, gadolinium chloride (GdCl3) was injected intravenously via the tail vein at 7.5 mg/kg body wt. 1 and 2 days before surgery. (omitted)

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Role of Kupffer Cells in Hepatic Drug Metabolizing Dysfunction during Polymicrobial Sepsis

  • Lee, Sang-Ho;Kim, Joo-Young;Eum, Hyun-Ae;Lee, Sun-Mee
    • Proceedings of the PSK Conference
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    • pp.229-229
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    • 2002
  • Although hepatocellular dysfunction occurs during sepsis. the mechanism responsible for this remains unclear. Since Kupffer cells provide signals that regulate hepatic response in endotoxin and inflammation. the aim of this study was to investigate the role of Kupffer cells in the alterations in the hepatic microsomal drug metabolizing function during sepsis. Rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP)followed by fluid resuscitation. (omitted)

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Kupffer Cells Are Responsible for Producing Hepatic Microsomal Drug Metabolizing Dysfunction during Trauma and Sepsis

  • Lee, Sang-Ho;Kim, Joo-Young;Kim, Sung-Ho;Eum, Hyun-Ae;Lee, Sun-Mee
    • Proceedings of the PSK Conference
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    • pp.301.3-302
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    • 2002
  • Sepsis remains the leading cause of morbidity and mortality following trauma. Although hepatocellular dysfunction occurs during trauma and sepsis. the mechanism responsible for this remains unclear. We investigated the role of Kupffer cells in the alterations in microsomal drug metabolizing function during trauma and sepsis. Rats were subjected to trauma by femur fracture (FFx). After 72h, polymicrobial sepsis was induced by cecal ligation and puncture(CLP). (omitted)

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Hepatic Injury Studied in Two Different Hypoxic Models (저산소 모델에 따른 간장 기능 손상에 관한 연구)

  • 윤기욱;이상호;이선미
    • Biomolecules & Therapeutics
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    • v.8 no.2
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    • pp.119-124
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    • 2000
  • We hypothesized that the extent of hypoxic injury would be involved in reduction of oxygen delivery to the tissue. Livers isolated from 18 hr-fasted rats were subjected to $N_2$-induced hypoxia or low flow hypoxia. Livers were perfused with nitrogen/carbon dioxide gas for 45min or perfused with normoxic Krebs-Henseleit bicarbonate buffer (KHBB) at low flow rates around 1 ml/g liver/min far 45min, which caused cells to become hypoxic because of insufficient delivery of oxygen. When normal flow rates(4 ml/g liver/min) of KHBB (pH 7.4, 37$^{\circ}C$, oxygen/carbon dioxide gas) were restored for 30min reoxygenation injury occurred. Lactate dehydrogenase release gradually increased in $N_2$-induced hypoxia, whereas it rapidly increased in low flow hypoxia. Total glutathione in liver tissue was not changed but oxidized glutathione markedly increased after hypoxia and reoxygenation, expecially in $N_2$-induced hypoxia. Similarly, lipid peroxidation in liver tissue significantly increased after hypoxia and reoxygenation in low flow hypoxia. Hepatic drug metabolizing functions (phase I, II) were suppressed during hypoxia, especially in $N_2$-induced hypoxia but improved by reoxygenation in both models. Our findings suggest that hypoxia results in abnormalities in drug metabolizing function caused by oxidative stress and that this injury is dependent on hypoxic conditions.

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Lipid Peroxidation of Hepatic Microsomal Drug-Metabolizing System in Hepatic Ischemia ands Reperfusion (간장내 허혈 및 재관류시 약물대사 효소계의 지질 과산화에 관한 연구)

  • 이선미;박미정;이상호;박두순;조태순
    • Biomolecules & Therapeutics
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    • v.2 no.2
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    • pp.141-148
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    • 1994
  • This study was done to determine whether specific alterations exist in hepatic microsomal function after varying periods of ischemia (IS) and reperfusion (RP) during microsomal lipid peroxidation occurs. Rats were pretreated with $\alpha$-tocopherol to inhibit lipid peroxidation or with vehicle (soybean oil). Control animals were time-matched sham-ischemic animals. Four groups of animals were studied: Group 1 (sham), group 2 (30 mins IS), group 3 (60 mins IS) and group 4 (90 mins IS). After 1, 5 or 24 hr of reperfusion, liver microsomes were isolated and cytochrome P-450s were studied. In all vehicle-treated ischemic rats, serum ALT levels peaked at 5 hr and were significantly reduced by $\alpha$-tocopherol pretreatment. Similarly, microsomal lipid peroxidation was elevated in all vehicle-treated ischemic animal groups, but this elevation was prevented by $\alpha$-tocopherol pretreatment. Cytochrome P-450 content was significantly decreased in both group 3 and group 4. In all vehicle-treated ischemic animal groups, aminopyrine N-demethylase activity was significantly decreased for the entire reperfusion period. $\alpha$-Tocopherol inhibited reductions of cytochrome P-450 content and aminopyrine N-demethylase activity at both 1 hr and 5hr of reperfusion but did not affect the reduced levels of cytochrome P-450 content and aminopyrine N-demethylase activity at 24 hr of reperfusion. Aniline p-hydroxylase activity was significantly decreased in group 4, whereas it was increased in group 3. These decreases and increases were prevented by $\alpha$-tocopherol pretreatment. Our finding suggests that abnormalities in microsomal drug metabolizing function occur during hepatic ischemia and reperfusion in vivo and this is attributed to microsomal lipid peroxidation.

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Inhibition of hepatic microsomal drug-metabolizing enzymes by imperatorin

  • Shin, Kuk-Hyun;Woo, Won-Sick
    • Archives of Pharmacal Research
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    • v.9 no.2
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    • pp.81-86
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    • 1986
  • The effect of imperatorin on hepatic microsomal mixed function oxidases (MF0) was investigated. On acute treatment, imperatorin (30 mg/kg, i.p) caused a significant reduction in activities of hepatic aminopyrine N-demethylase, hexobarbital hydroxylase and aniline hydroxylase as well as cytochrome p0450 content in rats and mice. Kinetic studies on rat liver enzymes revealed that imperatorin appeared to be a competitive inhibitor of aminopyrine N-demethylase (Ki,0.007 mM), whereas a non-competitive inhibitor of hexobarbital hydroxylase (Ki, 0.0148 mM). Imperatorin also inhibited non-competitively aniline metabolism (Ki 0.2 mM). Imperatorin binds to phenobarbital-induced cytochrome p-450 to give a typical type 1 binding sepctrum (max. 388nm, min 422 nm). Multiple administrations of imperatorin (30 mg/kg. i. p. daily for 7 days) to mice shortended markedly the duration of hexobarbital narcosis and increased activities of hepatic aminopyrine N-demethylase and hexobarbital hydroxylase and the level of cytochrome p-450 where as aniline hydroxylase activity was unaffected.

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Pharmacologic Activities of Saikosaponins(I) -Effects on Drug Metabolizing Enzymes Modification and Liver Toxicities due to Acetaminophen- (시호(柴胡) 사포닌류(Saikosaponins)의 약리작용(I) -Acetaminophen에 의한 약물대사계의 변화 및 간독성에 미친 영향-)

  • Lee, Jeong-Sik;Lee, Chung-Kyu;Choi, Jong-Won
    • Korean Journal of Pharmacognosy
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    • v.24 no.1
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    • pp.69-77
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    • 1993
  • Saikosaponins, originally isolated from Bupleuri Radix, were reported to exhibit diverse biological activities especially concerning with liver function. To elucidate the mode of protective action of saikosaponins on liver injury due to the acetaminophen administration, effects on drug metabolizing enzymes system and some transferase activities were checked. As the result, activities of transferase were shown to be strengthened by saikosaponin treatments significantly.

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Changes in drug metabolism during hypoxia/reoxygenation in isolated perfused rat

  • Seo, Min-Young;Cho, Tai-Soon;Lee, Sun-Mee
    • Proceedings of the Korean Society of Applied Pharmacology
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    • pp.98-98
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    • 1997
  • This study was done to investigate the effect of vitamin E on hypoxia/reoxygenation-induced hepatic injury in isolated perfused rat liver. Rats were pretreated with vitamin E or vehicle(soybean oil). Isolated livers from fasted 18 hours were subjected to 45min of low flow hypoxia or N$_2$ hypoxia followed by reoxygenation for 30min. The perfusion medium used was KHBB(pH 7.4) and 50${\mu}$㏖/$\ell$ of ethoxycoumarin was added to the perfusate to determine the ability of hepatic drug-metabolizing systems, In low flow hypoxia model, total glutathione and oxidised glutathione levels were significantly increased by hepoxia/reoxygenation with slight increase in LDH levels. These increases were prevented by vitamin E pretreatment. In N$_2$ hypoxia model, LDH, total glutathione and oxidized glutathione levels were increased significantly by hypoxia but restored to normal level by reoxygenation. Vitamin E had little effect on this hypoxic damage. There were no significant changes in the rate of hepatic oxidation of 7-EC to 7-HC in both hepoxic models. But, the subsequent conjugation of 7-HC by sulfate or glucuronic acid were significantly decreased by hypoxia, but restored by reoxygenation in both hypoxia models. As opposed to our expectation, treatment with vitamin E aggrevated the decrease of the rate of conjugation and even inhibited the restoration by reoxygenation. Our findings suggest that hypoxia/reoxygenation diminishes phase II drug metabolizing function and this is, in part, related to decreased energy level.

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The Beneficial Effect of Trolox on Sepsis-Induced Hepatic Drug Metabolizing Dysfunction

  • Park, Sang-Won;Lee, Sun-Mee
    • Archives of Pharmacal Research
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    • v.27 no.2
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    • pp.232-238
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    • 2004
  • Trolox is a hydrophilic analogue of vitamin E. The aim of this study was to investigate its effects on hepatic injury, especially alteration in cytochrome P450 (CYP)-dependent drug metabolism during polymicrobial sepsis. Rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). The rats were treated intravenously with Trolox (2.5 mg/kg) or vehicle, immediately after CLP. Serum aminotransferases and lipid peroxidation levels were markedly increased 24 h after CLP. This increase was attenuated by Trolox. Total CYP content and NADPH-P450 reductase activity decreased significantly 24 h after CLP. This decrease in CYP content was attenuated by Trolox. At 24 h after CLP, there was a significant decrease in the activity of these CYP isozymes: CYP1A1, 1A2, 2B1, and 2E1. However, Trolox differentially inhibited the decrease in CYP isozyme activity. Trolox had little effect on the decrease in CYP1A1 activity but Trolox significantly attenuated decreases in CYP1A2 and 2E1 activities. In fact, Trolox restored CYP2B1 activity to the level of activity found in control rats. Our findings suggest that Trolox reduces hepatocellular damage as indicated by abnormalities in hepatic drug-metabolizing function during sepsis. Our data also indicates that this protection is, in part, caused by decreased lipid peroxidation.