• Journal of Nutrition and Health
• /
• 제38권9호
• /
• pp.689-697
• /
• 2005

This study was conducted to fine out the preventive effects of chitosan and chitosan oligomer on the disorders of hepatic functions and lipid metabolism induced by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) using adult male rats (SD) for four weeks. Rats were fed chitosan ($4\%$) or chitosan oligomer ($4\%$) diets respectively before 3weeks of TCDD treatment (50 ug/kg BW) by intraperitoneal injection and then continually supplied these diets for one week until being sacrificed. The elevation of serum total and LDL cholesterol levels induced by TCDD treatment was significantly reduced in the rats fed chitosan diets. The increment of liver triglyceride levels caused by TCDD treatment was tended to suppress in all rats fed chitosan and chitosan oligomer diets. Fecal total lipid and cholesterol excretion were high levels in the rats fed chitosan diets. The hepatic cytosolic catalase activities significantly decreased by TCDD treatment appeared recovering trend by chitosan diets. In hepatic microsomal cytochrome p-450, NADPH cytochrome p-450 reductase, ethoxycoumarin-o-deethylase (ECOD) and benzphetamin N-demethylase (BPND) chitosan than chitosan oligomer diets apparently decreased the increasing levels by TCDD treatment. In histochemical observation the fat droplets and apoptosis of hepatocytes by TCDD treatment were markedly alleviated by chitosan and chitosan oligomer diets. These results indicate that chitosan, more than chitosan oligomer can exert preventive effects on some disorders of hepatic functions and lipids accumulation by TCDD.

• Biomolecules & Therapeutics
• /
• 제3권4호
• /
• pp.304-310
• /
• 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.

• BMB Reports
• /
• 제32권3호
• /
• pp.232-238
• /
• 1999

Sex differences in the induction of microsomal cytochrome P-450 (CYP) and the activities of several related enzymes of Sprague-Dawley rats treated with 1-bromopropane (1-BrP) were investigated. Male and female rats were exposed to 50, 300, and 1800 ppm of 1-BrP per kg body weight (6 h a day,S days a week, 8 weeks) by inhalation. The mean body weight of 1-BrP treated groups increased according to the day elapsed, but four and five weeks respectively after the start of the exposure, the mean body weight of male and female rats had significantly reduced in the group treated with 1800 ppm 1-BrP compared with the control group (p<0.01). While the relative weights of liver increased in both sexes, statistical significance in both sexes was found only in the group receiving 1800 ppm/kg of 1-BrP (p<0.01). The total contents of CYP, $b_5$, NADPH-P-450 reductase, NADH $b_5$ reductase, ethoxyresorufin-O-deethylase (EROD), pentoxyresorufin-O-dealkylase (PROD), and p-nitrophenol hydroxylase (pNPH) activities were examined for the possible effects of 1-BrP. No significant changes in the CYP and $b_5$ contents, NADPH-P-450 reuctase, NADH $b_5$ reductase, ethoxyresorufin-O-deethylase (EROD), and pentoxyresorufin- O-dealkylase (PROD) were observed between the control and treated groups. The activity of pNPH increased steadily with the increase in the concentration of 1-BrP in both sexes, but was significantly increased only in the 1800 ppm-treated group of male rats (p<0.05). When Western blottings were carried out with three monoclonal antibodies (MAb 1-7-1, MAb 2-66-3, and MAb 1-98-1) which were specific against CYP1A1/2, CYP2B1/2, and CYP2E1, respectively, a strong signal corresponding to CYP2E1 was observed in microsomes obtained from rats treated with 1-BrP. Glutathione S-transferase (GST) activity and the content of lipid peroxide significantly increased in the treated groups compared with the control group (p<0.05). These results suggest that 1-BrP can primarily induce CYP2E1 as the major form and that GST phase II enzymes play important roles in 1-BrP metabolism, showing sex-dependence in the metabolic mechanism of 1-BrP in the rat liver.

• 생명과학회지
• /
• 제12권2호
• /
• pp.136-143
• /
• 2002

자보양영환은 자보폐간의 효능이 있어 간허증상의 치료제로 사용되었던 전통약물로 잘 알려져 있다. 따라서 본 연구에서는 사염화탄소로 간 손상을 유도한 흰쥐에서 자보양영환의 물추출물이 간 보호효과가 있는지 알아보았다. 사염화탄소의 1회 복강투여는 혈청 aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP)의 유의적인 증가가 관찰되어 사염화탄소에 의한 간 손상이 유발되었음을 알 수 있었다. 자보양영환 물 추출물(300, 600, and 1200 mg/kg, 7 days)을 전 처리한 횐쥐에서는 사염화탄소 단독 투여군인 대조군에 비해 AST, ALT, ALP의 유의한 감소양상이 관찰되었다. 또한 사염화탄소의 투여는 microsome의 지질과산화가 유도되었으며, 이물질대사효소(cytochrome P450 및 P450 reductase)의 유의한 감소가 확인되었다. 자보양영환 물추출물의 경구투여는 간의 지질과산화 지표인 microsome의 TBARS 생성을 억제하였으며 cytochrome P450 및 P450 reductase 활성도가 대조군에 비해 유의한 증가되어 정상수준으로 회복되었다. 자보양영환 추출물의 투여는 사염화탄소의 투여에 따른 생화학적 지표들의 변화를 억제하는데, 이러한 실험결과에서 자보양영환의 물추출물은 사염화탄소로 유도한 간 독성에 대하여 해독작용 및 간 보호효과가 있는 것으로 판단된다.

• 약학회지
• /
• 제43권6호
• /
• pp.827-833
• /
• 1999

In this study, we have investigated the effect of Biphenyl Dimethyl Dicarboxylate (DDB), a synthetic analogue of Schizandrin C isolated from Schizandrae Fructus on cytochrome $P_450$ lAl and 2Bl, and the protective mechanism against $CCl_4-induced$ hepatotoxicity in rat liver. After DDB was administered into male rats for different periods of time (1~7 days) and with different doses (25, 50, 100 and 200 mg/kg), mRNA levels of CYPlAl were measured by polymearse chain reaction (PCR) and assayed the activities of CYPlAl specific ethoxyresorufin-O-dealkylase (EROD) and CYP2Bl specific benzyloxyresorufin-O-dealkylase (BROD). DDB treatment resulted in increase in CYP2Bl mRNA level and BROD activity, whereas there was no change in CYPlAl mRNA level and EROD activity. This effect of DDB was time-and dose-dependent and reached maximal level by 3 day and 200 mg/kg treatment. In addition, rats were pre-treated with DDB at doses of 25, 50 or 100 mg/kg daily for 4 days, 3-hr after final treatment on the 4th day, $CCl_4$ 0.3ml/kg was intraperitonially injected into the rats to examine the effect of DDB on $CCl_4-induced$ hepatic injury. Serum levels of ALT and AST were determined and histopathological examination was done in rat liver. Furthermore, we have measured hepatic microsomal malondialdehyde(MDA) level, a parameter of lipid peroxidation. Based on serum ALT level and lipid peroxidation, pretreatment of DDB, 50 mg/kg appeared the most protective effect against $CCl_4-induced$ heapatotoxity. These results indicate that DDB stimulates CYP2Bl mRNA level and BROD activity in time and dose dependent manner and suggest that protective effect of DDB on $CCl_4-induced$ hepatotoxicity may be mediated through free radical scavenging.

• 대한수의학회지
• /
• 제35권3호
• /
• pp.489-496
• /
• 1995

Artemisia messes-schmidiana var viridis(Compositae) has been used for jaundice, hepatitis, diuretic and liver cirrhosis etc. 1-naphthylisothiocyanate(ANIT) has been used as a model compound to study mechanisms of intrahepatic cholestasis in laboratory animals as rat and mouse. The purposes of present study are to examine pharmacological effects of Artemisia messes-schmidiana var viridis water extract(AMWE) on alterations of triacylglycerol, cholesterol, protein, albumin and A/G ratio levels in serum, of histopathological appearances of liver, and that of hepatic microsomal cytochrome P-450 contents. Increased serum triacylglycerol levels by ANIT were significantly decreased with AMWE. However, AMWE posttreatment aggravated ANIT-induced cholesterol increase. Serum total protein and albumin contents, and A/G ratio were decreased in all ANIT-treated groups, and there were increased compared with control by AMWE posttreatment. Hepatic microsomal cytochrome P-450 contents were decreased in either AMWE and ANIT treatment, which greatly increased with AMWE pretreatment. On the other hand, in histological findings, our results shown that ANIT induced increase of lipid droplets and widening of sinusoidal capillary and these phenomena were disappeared with AMWE treatment. In conclusion, AMWE have choleresis effect. Also, AMWE improved lipid metabolism, protection and regeneration of hepatocytes in ANIT-induced cholestasis.

• 생약학회지
• /
• 제23권2호
• /
• pp.81-88
• /
• 1992

The effects of scoparone, one of coumarin derivative on the hepatic bromobenzene metabolizing enzyme system was estimated in rats. Scoparone pretreatment revealed dose-dependently the recovery of decrease in epoxide hydrolase activity due to the bromobenzene(310 mg/kg, i.p.) treatment. And also scoparone and scopoletin (each 5mg/kg, p.o.) pretreatments showed two times increase in the $V_{max}$ values compared to those of bromobenzene-treated group which were calculated from tripartite reciprocal plots. The mode of protective effect of scoparone against bromobenzene induced toxicity is considered to be due to the induction of microsomal enzyme activity by scopoletin, the intermediate metabolite of scoparone. The changes in cytochrome P-450 activity, aminopyrine N-demethylation, aniline hydroxylation and glutathione S-transferation in scoparone-treated group were not significantly different from those of the control group.

• Natural Product Sciences
• /
• 제10권4호
• /
• pp.182-189
• /
• 2004

To find the action mechanism of the MeOH extract (LFS) of Ligularia fischeri var. spiciformis herbs (Compositae) and its active component, 3,4-dicaffeoylquinic acid (DCQA) on antihepatotoxicity, the effect was investigated on hepatic lipid perxodation and drug-metabolizing enzyme activities in acetaminophen-treated rat. Pretreatment with 250 mg/kg LFS (p.o.) and 10 mg/kg DCQA (p.o.) significantly decreased hepatic lipid peroxidation caused by acetaminophen injection. Further, LFS and DCQA inhibited hepatic microsomal enzyme activation such as hepatic P-450 cytochrome $b_5$, aniline hydroxylase and aminopyrine N-demethylase, suggesting that the two substances might effectively prevent the metabolic activation or scavenge electrophilic intermediates capable of causing hepatotoxicity. Both LFS and DCQA increased hepatic glutathione content and glutathione reductase activity, indicating that both resultantly prevented hepatotoxicity via antioxidative mechanism. Therefore, it was found that LFS had antihepatotoxicity based on the antioxidative action of DCQA.

• Toxicological Research
• /
• 제23권4호
• /
• pp.289-299
• /
• 2007

Lipopolysaccharide (LPS) endotoxin is an active component in the outer membrane of Gram-negative bacteria. LPS is usually used as an inflammatory animal model. During the inflammation, diarrhea and changes in plasma proteins, in hepatic and/or intestinal microsomal cytochrome P450 (CYP) isozymes, and in the renal and/or biliary excretion of drugs have been reported. Thus, in rats pretreated with lipopolysaccharide endotoxin isolated from Klebsiella pneumoniae (KPLPS rats), the absorption, distribution, metabolism, and excretion of drugs could be expected to be altered. Interestingly time-dependent effects on the hepatic CYP isozymes have been reported in KPLPS rats. Thus, in KPLPS rats, the pharmacokinetics of drugs which are mainly metabolized via CYP isozymes could be expected to be time-dependent. In this review, an attempt to explain changes in pharmacokinetics of drug reported in the literature was made in terms of CYP isozyme changes or urinary and/or biliary excretion changes in KPLPS rats.

• 약학회지
• /
• 제44권4호
• /
• pp.300-307
• /
• 2000

Expression of xenobiotic-metabolizing enzymes can be altered by xenobiotics, which represents changes in the production of reactive metabolic intermediates as well as toxicities in tissues. Metabolic intermediates derived from xenobiotics are considered to produce the reactive oxygen species including drug free radicals and hydroxyl free radicals, which would be ultimately responsible for drug-induced toxicities. The effects of 1,2-benzothiazine anti-inflammatory agents on the expression of xenobiotic-metabolizing enzymes including major cytochrome P450s, microsomal epoxide hydrolase (mEH) and glutathione S-transferase (GST) were studied in the liver with the aim of providing the part of information on potential production of reactive metabolites and hepatotoxicity by the agents. The synthetic compounds 24, 36 and 39 exhibited anti-inflammatory effects in rats as assessed by the Randall-Selitto method. The anti-inflammatory effect was detected as early as at 30 min after gavaging the agents with the ED5O being noted at 80 mg/kg, which was comparable to that of ibuprofen. Treatment of rats with each compound (100 mg/kg, 3d) resulted in no significant induction in the immunochemically-detectable cytochromes P45O 1A1/2, P450 2B1/2, P45O 2 Cl1 and P45O 2El. Changes in the mEN expression were also minimal, as evidenced by both Western blot and Northern blot analyses. Hepatic GST expression was slightly increased by the agents: GST Ya protein and mRNA expression was ～1.5-fold increased after treatment with compounds 24 and 39, whereas GST Yb1/2 and Yc1/2 mRNA levels were elevated 2- to 3-fold. In summary the effects of the synthetic 1,2-benzothiazines on the expression of major P45O, mEH and G57 were not significant, providing evidence that metabolic activation of the agents, potential drug interaction and hepatotoxicity would be minimal.