• Title/Summary/Keyword: drug metabolizing function

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Effect of Vitamin C on Hepatic Biliary and Microsomal Function in Hepatic Ischemia/reperfusion (간장 허혈 및 재관류시 Vitamin C가 간장 기능에 미치는 영향)

  • 김순애;서민영;염동호;조태순;이선미
    • Biomolecules & Therapeutics
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    • v.3 no.4
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    • pp.304-310
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    • 1995
  • This study was done to investigate the effect of vitamin C on hepatic biliary and microsomal function during ischemia and reperfusion. Rats were treated with vitamin C(20, 100, 400, 1600 mg/kg) or with vehicle(saline) and then subjected to 60 min no-flow hepatic ischemia in vivo. Control animals were time-matched sham ischemic animals. After 1 or 5 hr of reperfusion, bile was collected, blood was obtained from the abdominal aorta, and liver microsomes were isolated. In vehicle-treated ischemic rats, serum ALT and AST levels peaked at 5 hr and were significantly attenuated by vitamin C 20 mg/kg and 100 mg/kg treatment. Similarly, hepatic wet weight-to-dry weight ratio was decreased in the vehicle-treated ischemic group. Vitamin C 20 mg/kg and 100 mg/kg treatment minimized the increase in this ratio. Lipid peroxidation was elevated in vehicle-treated ischemic group, but this elevation was also inhibited by vitamin C 20 mg/kg and 100 mg/kg treatment. Bile flow and cholate output, but not bilirubin output, were markedly decreased by ischemia/reperfuzion. Vitamin C 20 mg/kg and 100mg/kg treatment restored the secretion but vitamin C 1600 mg/kg reduced the cholate output. Cytochrome P-450 content was decreased by ischemia/reperfusion and restored by vitamin C 20 mg/kg and 100 mg/kg treatment to the level of sham operated group but decreased by vitamin C 1600 mg/kg. Aminopyrine N-demethylase activity was decreased and aniline p-hydroxylase activity was increased by ischemia/reperfusion. The changes in the activities of aminopyrine were prevented by vitamin C 20 mg/kg and 100 mg/kg treatment, but not by 400 mg/kg and 1600 mg/kg treatment. Our findings suggest that ischemia/reperfusion diminishes hepatic secretory functions as well as microsomal drug metabolizing systems, small doses(20, 100 mg/kg) of vitamin C significantly ameliorates and large doses(400, 1600 mg/kg) of vitamin C aggravated these ischemia/reperfusion-induced changes.

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Comparative liver drug metabolizing enzymes activities between Korean native cattle and swine (한우와 돼지에서 간의 약물 대사효소의 활성 비교)

  • Lee, Gwan-bok;Yun, Hyo-in;Park, Seung-chun;Kim, Min-kyu;Lee, Rae-kyung;Cho, Joon-hyung;Lee, Dong-woo
    • Korean Journal of Veterinary Research
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    • v.38 no.1
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    • pp.17-28
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    • 1998
  • Drug-metabolizing activities of Korean native cattle and swine were investigated from viewpoints of the cytochrome P-450's level, their dependent mixed function oxidase activities, the reactive oxygen species formation and cytosolic enzyme acitivities from each liver homogenates. Level of cytochrome P-450 in the liver microsome of Korean native cattle was $0.28{\pm}0.05nmole/mg$ and that in pigs $0.35{\pm}0.03nmole/mg$. Level of cytochrome $b_5$ of Korean native cattle was $0.24{\pm}0.06nmole/mg$, and that of pigs $0.2{\pm}0.05nmole/mg$, showing no difference between two species. NADPH P-450 reductase were higher in Korean native cattle ($58.3{\pm}5.3nmole/mg/min$) than in pigs ($29.9{\pm}3.8nmole/mg/min$)(p<0.01). The activities of cytochrome P-450 dependent monooxygenases such as ethoxyresorufin O-deethylase (cattle, $96.5{\pm}12.5nmole/mg/min$ ; pigs, $13.6{\pm}2.1nmole/mg/min$), N-benzphetamine N-demethylase (cattle, $5.23{\pm}0.82nmole/mg/min$ ; pigs, $0.76{\pm}0.3nmole/mg/min$) and aniline hydroxylase (cattle, $0.95{\pm}0.1nmole/mg/min$ ; pigs, $0.33{\pm}0.08nmole/mg/min$) were much higher in Korean native cattle than in swine(p<0.01). However, the activity of testosterone $7{\alpha}$-hydroxylase was higher in swine ($90.4{\pm}1.2nmole/mg/min$) than cattle (cattle, $32.8{\pm}1.2nmole/mg/min$). Interestingly, testosterone $16{\alpha}$-hydroxylase, a marker enzyme for P-450 IIA was not detected in both animal species. These results suggest that Korean native cattle and pigs have high contents of P-450 IA1 and P-450 IIIA. Total sulfhydryl compound (cattle, $10.3{\pm}1.1nmole/mg$ ; Pigs, $14.5{\pm}1.8nmole/mg$) and glutathione related enzymes except glutathione reductase (cattle, $38.1{\pm}7.9nmole/mg/min$; swine, $22{\pm}3.6nmole/mg/min$) showed higher levels in swine than in Korean native cattle. Superoxide dismutase (cattle, $7.64{\pm}0.84nmole/mg/min$ ; pigs, $4.47{\pm}0.94nmole/mg/min$) and catalase (cattle, $30.4{\pm}3.7nmole/mg/min$ ; pigs, $17.2{\pm}1.8nmole/mg/min$) were remarkably higher in Korean native cattle than in swine (p<0.05).

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Nrf2 Knockout Mice that Lack Control of Drug Metabolizing and Antioxidant Enzyme Genes - Animals Highly Sensitive to Xenobiotic Toxicity

  • Enomoto, Akiko;Itoh, Ken;Harada, Takanori;Yamamoto, Masayuki
    • Toxicological Research
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    • v.17
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    • pp.299-304
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    • 2001
  • Xenobiotics and their reactive intermediates bind to cellular macromolecules and/or generate oxidative stress. which provoke deleterious effects on the cell function. Induction of xenobiotic-biotrans-forming enzymes and antioxidant molecules is an important defense mechanism against such insults. A group of genes involved in the defense mechanism. e.g. genes encoding glutathione S-transferases. NAD(P)H: quinone oxidoreductase, UDP-glucuronosyltransferase (UDP-GT) and ${\gamma}$-glutamylcysteine synthetase (GGCS). have a common regulatory sequence, Antioxidant or Electrophile Responsive Element (ARE/EpRE). Recently. Nrf2. discovered as a homologue of erythroid transcription factor p45 NF-E2, was shown to bind ARE/EpRE and induce the expression of these defense genes. Mice that lack Nrf2 show low basal levels of expression and/or impaired induction of these genes. which makes the animals highly sensitive to xenobiotic toxicity. Indeed. we show here that nrf2-deficient mice had a higher mortality than did the wild-type mice when exposed to acetaminophen (APAP). Detailed analyses of APAP hepatotoxicity in the nrf2 knockout mice indicate that a large amount of reactive APAP metabolites was generated in the livers due to the impaired basal expression of two detoxifying enzyme genes, UDP-GT (Ugt1a6) and GGCS. while the cytochrome P450 content was unchanged. Thus. the studies using the nrf2 knockout mice clearly demonstrate significance of the expression of Nrf2-regulated enzymes in protection against xenobiotic toxicity.

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Effect of Capsaicin on L-Ascorbic Acid Level in Various Tissues and Its Urinary Excretion in Rats

  • Yu, Rina;Kurata, Tadao
    • Preventive Nutrition and Food Science
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    • v.1 no.1
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    • pp.69-74
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    • 1996
  • Capsaicin(CAP) is a pungent ingredient of hot pepper that has been used as a spicy food additive, pre-servative, and medicine. In this study, the effect of CAP on L-ascorbic acid(AsA)level in various tissues as well as its urinary excretion. and drug-metabolizing enzyme activity in rats were investigated. Rats fed AsA-deficient diets for 17days were injected intraperitoneally with 1mg of CAP in 0.5ml of ethanol-Tween 80-saline(20 :10 : 70, v/v/v). Control rats received the equal volume of the same solution without CAP. Urine was collected for 3 day after the CAP injection, and after 5 days tissues were removed; their AsA contents were measured by high performance liquid chromatography combined with and electrochemical detector. In addition, hepatic microsomal ethoxyresorfin O-deethylase(EROD) activity as measured. Urinary AsA excretion changed significantly following CAP injection. One and two days after CAP injection, the urinary AsA increased 2-and 3-fold in the CAP injected group, compared to the control, but the contents of adrenal glands and brain were lower than those of the control Dehydroascorbic acid contents in adrenal glands of the CAP injected group were higher than that of the control These results suggested that a single large dose of CAP could temporarily cause the redistribution of AsA in tissues accompanying by its urinary excretion, by affecting probably a biological system including mixed function oxygenase system(MFOS)

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Effect of vitamin C on hepatic drug metabolism in hypoxia/reoxygenation

  • Lee, Hae-;Jung, Ju-Yeon;Han, Suck-Hee;Cho, Tai-Soon;Lee, Sun-Mee
    • Proceedings of the Korean Society of Applied Pharmacology
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    • 1998.11a
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    • pp.191-191
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    • 1998
  • It has been hypothesized that formation of oxygen-derived free radicals may play an important part in ischemically induced tissue injury. In this study, the effects of vitamin C treatment on hepatic reperfusion model were investigated. Livers isolated from 18 hrs fasted rats were subjected to low flow hypoxia (1 $m\ell$/g liver/min, for 45min) followed by reoxygenation (for 30min). The perfusion medium used was Krebs-Henseleit bicarbonate buffer (KHBB, pH 7.4) and vitamin C (0.25, 0.5, 1.0 and 2.0 mM) was added to perfusate. 7-Ethoxycoumarin was used as substrate of phase and metbolism. After hypoxia oxygen consumption significantly dropped but vitamin C 0.25, 0.5 and 1.0 mM treatments restored oxygen consumption to the level of control group. LDH and lipid peroxidation were not changed in all experimental groups. Oxidation, phase metabolism, significantly decreased following hypoxia but improved during reoxygenation. Vitamin C 0.25 mM treatment significantly improved the oxidation of 7-ethoxycoumarin during hypoxia and reoxygenation, but the oxidation significantly decreased by vitamin C 2.0 mM treatment. Similarly, sulfate conjugation decreased in hypoxic group, but this decrease was inhibited by vitamin C 0.25, 0.5 and 1.0 mM treatments. Our findings suggest that hypoxia/reoxygenation diminishes hepatic drug metabolizing function, vitamin C at concentration of 0.25-1.0 mM ameliorates but at higher concentration aggravates these hypoxia/reoxygenation-induced changes.

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Potentiation of Carbon Tetrachloride Hepatotoxicity induced by Repeated Physical Exercise in adult Female rats (백서의 반복적인 육체운동에 의한 사염화탄소 간독성의 증폭효과)

  • Kim, Su-Nyeon;Kim, Young-Chul
    • Toxicological Research
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    • v.8 no.2
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    • pp.265-272
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    • 1992
  • Effects of repeated physical exercise on the carbon tetrachloride ($CCl_4$) hepatotoxicity were examined in adult female rats. Rats were introduced into a cylindrical rotating cage and forced to exercise for 1 hr each day, 6days/week, for 5 consecutive weeks at a speed starting from 10m/min, increased by 1m/min per day until the speed reached 27m/min. Significantly less body weight gain was observed in the exercise group suggesting that physical fitness had been induced in these animals. Eighteen hours following termination of the last exercise bout rats were treated with $CCl_4$(2 mmol/kg.ip). The $CCl_4$-induced heptotoxicity was significantly potentiated in the repeated exercise group compared to the resting sedentary animals as determined by changes in serum sorbitol dehydrogenase (SDH), glutamic oxaloacetic transaminase(GOT), glutamic pyruvic transaminase (GPT), and glucose-6-phosphatase(G-6-Pase) activities when measured 24hrs following the $CCl_4$ treatment. Hepatic drug metabolizing activity was determined in order to elucidate the underlying mechanism of potentiating action of the $CCl_4$ hepatotoxicity induced by repeated physical exercise. Repeated exercise increased the hepatic microsomal cytochrome P-450 contents and aminopyrine N-demethylase activity. The results suggest that the potentiation of $CCl_4$ hepatotoxicity by repeated exercise is associated with induction of the mixed function oxidase (MFO) enzyme system mediating the metabolism of $CCl_4$ to its active metabolite(s).

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The Role of Oxygen Free Radicals and Phospholipase $A_2$ in Ischemia-reperfusion Injury to the Liver

  • Park, Mee-Jung;Cho, Tai-Soon;Lee, Sun-Mee
    • Archives of Pharmacal Research
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    • v.18 no.3
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    • pp.189-194
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    • 1995
  • The focus of this study was to investigate the influences of enzymatic scavengers of active oxygen metabolites and phospholipase $A_2$ inhibitor on hepatic secretory and microsomal function during hepatic ischemia/reperfusion. Rats were pretreated with free radical scavengers such as superoxide dismutase (SOD), catalase, deferoxamine and phospholipase $A_2$ inhibitor such as quinacrine and then subjected to 60 min. no-flow hepatic ischemia in vivo. After 1, 5 hr of reperfusion, bile was collected, blood was obtained from the abdominal aorta, and liver microsomes were isolated. Serum aminotransferase (ALT) level was increased at 1 hr and peaked at 5 hr. The increase in ALT was significantly attenuated by SOD plus catalase, deferoxamine and quinacrine especially at 5 hr of reperfusion. The wet weight-to-dry weight ratio of the liver was significantly increased by ischemia/reperfusion. SOD and catalase treatment minimized the increase in this ratio. Hepatic lipid peroxidiltion was elevated by ischemia/reperfusion, and this elevation was inhibited by free radical scavengers and quina crine. Bile flow and cholate output, but not bilirubin output, were markedly decreased by ischemia/reperfusion and quinacrine restored the secretion. Cytochrome $P_{450}$ content was decreased by ischemia/reperfusion and restored by free radical scavengers and quinacrine to the level of that of the sham operated group. Aminopyrine N-demethylase activity was decreased and aniline p-hydroxylase was increased by ischemia/reperfusion. The changes in the activities of the two enzymes were prevented by free radical scavengers and quinacrine. Our findings suggest that ischemia/reperfusion diminishes hepatic secretory functions as well as microsomal drug metabolizing systems by increasing lipid peroxidation, and in addition to free radicals, other factors such as phospholipase $A_2$ are involved in pathogenes of hepatic dysfunction after ischemia/reperfusion.

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Association between Genetic Polymorphisms of the CYP2C19, CYP2D6 and Types of Sasang Constitutional Medicine (약물대사효소 CYP2C19, CYP2D6의 다형성과 사상체질의 관련성 연구)

  • Lee, Sang-Gyu;Kim, Hyun-Ju;Park, Hye-Jung;Lee, Jung-Ho;Kwon, Deog-Yun;Joo, Jong-Cheon;Choi, Sun-Mi;Lee, Hye-Suk;Kim, Yun-Kyung
    • The Journal of Korean Medicine
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    • v.28 no.1 s.69
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    • pp.51-62
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    • 2007
  • Objectives . The types of Sasang constitutional medicine (SCM) have definite effect on response to herbal drugs. The majority of human P45O dependent xenobiotic metabolism is carried out by polymorphic enzymes which can cause abolished, altered or enhanced metabolism. Therefore, we evaluated the relation of major CYP2C19, 2D6 polymorphism with Sasang types. Methods : 214 healthy subjects were recruited with informed consent; 172 among them had Sasang diagnosis by QSCC2. CYP2D6, 2C19 polymorphism were determined by PCR-RFLP method. Results : None of the Sasang types showed significant difference in CYP2D6, 2C19 polymorphism. However, the Tae-um type showed relatively low frequency of CYP2D6 $^{*}$10/$^{*}$10 polymorphisms with low activity (p=0.110). In the So-yang type, specific $^{*}$3/$^{*}$3 genotype which is a poor metabolizer of CYP2C19$^{*}$3 was detected (p=0.078).Conclusion . These results suggest that the Tae-um type which is said to have high liver function in SCM has the tendency of high drug-metabolizing enzyme activity. With further study, the CYP polymorphism could serve as a scientific tool for SCM diagnosis.

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Search of Experimental Studies(35) on Anti aging and Anti oxidant in Korea (국내문헌(國內文獻)(35)에 나타난 항노화(抗老化) 및 항산화(抗酸化)의 실험적(實驗的) 연구(硏究)에 대(對)한 검색(檢索))

  • Ahn, Sang-Won;Lee, Cheol-Wan
    • The Journal of Korean Medicine
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    • v.19 no.2
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    • pp.373-390
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    • 1998
  • 35 theses conducted in Korea on the topic of senescence or anti-oxidant were classified on the basis of research methods, animals used for the experiments, and research items. Evaluating these research works with respect to the Free Radical Theory, the following conclusions were reached. 1. Of the 17 theses written in the Oriental medicine aspect, three theses used a single herb, nine theses used a complex prescription, four theses concentrated on the usage of the medicinal acupuncture, and one research paper focused on using scientific components. Common objection of these papers were on the verification of the efficacy of herbs. 2. Of the 18 these written in the Western medicine aspect, five theses used a single drug, seven theses conducted a research on the changes due to senescence, and 6 papers were on variety of topics. The main focus of these works were on the mechanism and pathology related to the senescence rather than on the suppression of senescence. 3. Among the theses written in the Oriental medicine perspective, a total of 48 herbs were utilized. 26 of these herbs has a tonification function on the Kidney. Six out of nine complex prescription mentioned above has a function of tonifying the Kidney. 4. With respect to the research subjects used on the experiments, 8 theses have used Senescence-Accelerated mice, 13 theses have used Sprague-Dawley mice, and remaining 7 papers have used human or other animals. 5. These are the categorization of the research items used: the weight (11) and weight changes of the visceral organs (9), the measurement of the content of peroxide-disease (9), the measurement of enzyme vitality (21), the blood and urine test (10), the experiment concerning immune system (3), the influence on the hepatic capability of metabolizing foreign substance (3), the effect on hepatic cell protection (3), the measurement of both the suppression of Free Radical and ability to create Free Radical (2), the measurement of effect of suppresing MDA(malondialdehyde) (4), the effect of eliminating DPPH Radical (2), and experiements about the functions (2). 6. The rate of vitalization of well known anti-oxidants such as Superoxide dismutase (SOD), Protein-bound SH, Nonprotein-bound SH, Glutathione(GSH), Catalase, and etc. were tested in 17 theses. Considering the conclusions mentioned above, the theses related to the senescence published in Korea elected different animals used for experiments, research items and the methods of research, the end result seems to be a lack of objectivity. Thus, I would argue that research methods to overcome such a deficiency need to be developed systematically.

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