Effects of Supplementation with a Schizandrin C Derivative DDB-mixed Preparation (DWP-04) on Antioxidant Activity in Cisplatin-induced Nephrotoxicity in Rats / 대한신장학회지

PURPOSE: This study investigated the effect of reducing cisplatin induced nephrotoxicity with DWP-04 that is the compound of Schizandrin C derivative biphenyldimethyl dicarboxylate (DDB), glutathione and selenium. For the purpose of observation is that how DWP-04 has influence on mechanism of reducing cisplatin induced nephrotoxicity with renal function test, free radical formation and detoxification enzyme system in renal tissue. METHODS: Five groups of rats were dosed with vehicle, cisplatin (2 mg/kg i.p.), cisplatin+DWP-04 (100, 200 mg/kg po), or cisplatin+sodium thiosulfate (200 mg/kg i.p.) daily for 4 weeks. RESULTS: Serum creatinine, lactate dehydrogenase and activity of hydroxy radical increased in the cisplatin group and suppressed in the cisplatin+DWP-04 group compared to the cisplatin group. The renal tissue concentration of lipid peroxidase and lipofuscin were increased in the cisplatin group compared to the other groups. The activity of aminopyrine N-demethylase, aniline hydroxylase, aldehyde oxidase and xanthine oxidase, of which free radical formation system in kidney was also decreased in the cisplatin+DWP-04 group compared to the cisplatin and cisplatin+sodium thiosulfate group. The activity of detoxification system of free radical, such as glutathione S-transferase, superoxide dismutase, catalase and glutathione peroxidase were markedly increased in the cisplatin+DWP-04 group than the cisplatin and the cisplatin+sodium thiosulfate group (p<0.05). CONCLUSION: It can be concluded that the mechanism of decreasing cisplatin-induced nephrotoxicity by DWP-04 is that the decreasing of the amount of lipid peroxide and lipofuscin in the renal tissue by increasing activity of the antioxidant defense system and the decreasing of reactive oxygen species by increasing detoxification enzyme activity.

Effects of ethyl acetate extract of Semen Hoveniae on liver microsomal cytochrome P450 isoenzyme in rat / 中国中药杂志

<p><b>OBJECTIVE</b>To investigate the effects of the ethyl acetate extract of Semen Hoveniae (ESH) on liver microsomal cytochrome P450 isoenzyme in rats.</p><p><b>METHOD</b>The rats were given orally the ESH in the doses of 0.14, 0.17, 0.2 g x kg (equivalent to the crude herb) for 10 days respectively. Rat liver microsomal cytochrome P450, NADPH-Cyt C reductase, erythromycin N-demethylase (ERD), Aniline hydroxylase (ANH), aminopyrine N-demethylase (ADM) activities were quantitated by UV chromatography. The levels of mRNA expression of CYP1A1, CYP2C11, CYP2E1 and CYP3A1 were detected by semi-quantitative reverse transcripatase-polymerase chain reaction (RT-PCR).</p><p><b>RESULT</b>The cytochrome P450 content, NADPH-Cyt C reductase activities and erythromycin N-demethylase (ERD) activities were not affected. Aniline hydroxylase (ANH) activities in liver were decreased by up to35.1%; aminopyrine N-demethylase (ADM) activitiesin liver were increased by up to 42.4%. The mRNA expression of CYP1A1, CYP2C11 and CYP3A1 were found to be increased markedly.</p><p><b>CONCLUSION</b>A specific effect of ESH on liver microsomal cytochrome P450 isoenzyme in rats was observed in this investigation. ESH had various effects on liver microsomal cytochrome P450 isoenzyme.</p>

Effects of kaempferol and quercetin on cytochrome 450 activities in primarily cultured rat hepatocytes / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To observe the effects of kaempferol and quercetin on the activity of cytochrome P450 in rat hepatocytes.</p><p><b>METHODS</b>Primarily cultured rat hepatocytes were exposed to kaempferol or quercetin in concentrations of 0.1, 1, 10 micromol/L for 12 h, 24 h and 48 h. Hepatocytes CYP isoemzymes-erythromycin N-demethylase (ERND) and aminopyrine N-demethylase (ADM) activities were determined by Nash methods. Erythromycin (10 micromol/L) was used as positive control and DMSO(0.1%) as solvent control.</p><p><b>RESULTS</b>Kaempferol and quercetin inhibited ENRD activity in a dose-and time-dependent manner. In dose-response study, the ENRD activities in kaempferol (0.1,1 and 10 micromol/L) treated groups were (0.088+/-0.008), (0.074+/-0.006) and (0.041+/-0.003)micromol/(mg.min(-1)), respectively. ENRD activity in quercetin treated groups at the same concentrations were (0.082+/-0.007), (0.063+/-0.007) and (0.034+/-0.005) micromol/(mg.min(-1)), respectively. In time-courses study, the ENRD activity exposed to 10 micromol/L kaempferol or quercetin for 12 h and 48 h were (0.053+/-0.006) and (0.037+/-0.007) micromol/(mg.min(-1)), or (0.067+/-0.005) and (0.032+/-0.004) micromol/(mg.min(-1)). ADM activity was inhibited only by kaempferol in 10 mol/L at 24 h, but was not significantly altered by quercetin at any concentration tested.</p><p><b>CONCLUSION</b>In the present condition, kaempferol and quercetin act as potential CYP3A4 inhibitors as they can significantly inhibit ENRD in primarily cultured rat hepatocytes.</p>

Modulation of the activities and mRNA expression of cytochrome P450 isoenzymes in rat liver by Panax gingseng and coadministration with Veratrum nigrum / 中国中药杂志

<p><b>OBJECTIVE</b>To study the modulatory effect of Panax gingseng and coadministration with Veratrum nigrum on the activity and mRNA expression of cytochrome P450 isoenzymes in rat liver.</p><p><b>METHOD</b>Rat liver microsomal cytochrome P450, b5, aminopyrine N-demethylase(APND), p-nitrophenol-hydroxylase(pNPH)activities were quantitated by UV chromatography. The mRNA expression level of five CYP isoenzymes CYP1A1, CYP2B1/2, CYP2C11, CYP2E1 and CYP3A1 were detected by semi-quantitative reverse transcriptase-polymerase chain reaction(RT-PCR).</p><p><b>RESULT</b>P. gingseng coadministrated with V. nigrum obviously decreased the P450 contents of liver microsomes, and the b5 contents. Both single and combined used inhibited the activities of aminopyrine N-demethylase. At the mRNA level, the expression of CYP2C11 markedly induced exposure to V. nigrum, but combinative groups decreased the expression of CYP2C11. The combination of P. gingseng and V. nigrum induced the expression of CYP1A1. P. gingseng has inhibitory effect on CYP2B1/2 and inductive effect used with V. nigrum. The combination of P. gingseng with V. nigrum also induced the expression of CYP3A1.</p><p><b>CONCLUSION</b>P. gingseng used singly has some different modulation effects compared with combinative used, which may occur because of drug-drug interaction based on cytochrome P450. To elucidate the drug-drug interaction, it needs further analysis and metabolism research.</p>

Effect of Korean Traditional Tea Materials Water Extract on Hepatic Oxygen Free Radical Generating and Scavenging Enzyme Activities in Lead Administered Rats

This study was designed to test the effect of Korean traditional tea materials on oxygen-free radical metabolism in lead (Pb) -administered rats. Male rats were divided into normal, Pb-control (Pb-Con) and Pb-water extract of green tea (Camellia sinensis; GT) , persimmon leaf (Diospyros kaki; PL) , safflower seed (Carhamus tinctorius: SS) , Du-Zhong (Eucommia ulmoides; EU) groups, respectively. Pb intoxication was induced by administration of lead acetate (25 mg/kg. B.W., oral) weekly. The extract was administered based on 1.26 g of raw material/kg B.W./day for 4 weeks. When the GT, PL, SS and EU were supplemented to the Pb-administered rats, hepatic lipid peroxide levels were significantly lower compared to the Pb-Con group. Hepatic cytochrom P-450 content and aminopyrine N-demethylase activity was lower in the Pb-Con group than in the normal group, whereas xanthine oxidase activity was significantly elevated in Pb-administered rats. The water extract of GT, PL, SS and EU supplementation attenuated changes in enzyme activities generating reactive oxygen species in the liver. Hepatic superoxide dismutase, catalase and glucose 6-phosphate dehydrogenase activities were significantly higher in the Pb-Con group than in the normal group, while monoamine oxidase activity also tended to increase in the Pb-administered rats. However, glutathione peroxidase and glutathione S-transferase activities, and glutathione content significantly decreased through Pb intoxication. The supplementation of GT, PL, SS and EU induced alleviation changes of hepatic antioxidant enzyme activity.

Effects of Angelica sinensis polysaccharides on hepatic drug metabolism enzymes activities in mice / 中国中药杂志

<p><b>OBJECTIVE</b>To study the effects of Angelica sinensis Polysaccharides (ASP) on the hepatic drug metabolism enzymes activities in normal mice and those prednisolone (PSL)-induced liver injury.</p><p><b>METHOD</b>The activities of phase II enzymes (GSH-related enzymes) and cytochrome P450 enzymes were measured by biochemical method.</p><p><b>RESULT</b>ASP increased the activities of glutathione S-transferase in liver microsomes and mitochondria. The cytochrome P450 content, NADPH-cytochrome c reductase, aminopyrine N-demethylase, and aniline hydroxylase activities in liver microsomes were also increased. PSL significantly increased serum ALT levels, and decreased the liver mitochondrial glutathione content. At the same time, other enzymes activities were all increased. When mice were treated with ASP 2.0 g.kg-1, the PSL-induced changes on cytochrome P450 enzymes, glutathione S-transferase, and GSH content were restored.</p><p><b>CONCLUSION</b>ASP can modulate the activities of drug metabolism enzymes.</p>

Effect of trichloroethylene (TCE) inhalation on biotransformation enzymes of rat lung and liver.

Trichloroethylene (TCE) is widely used as an industrial solvent and cleaning fluid. In the present study the toxic effects of TCE inhalation on pulmonary and hepatic biotransformation enzymes in rats have been investigated by assay of aniline hydroxylase (AH), aminopyrine-N-demethylase (APD), benzo-a-pyrene hydroxylase (BH) and glutathione-s-transferase (GST) activities and glutathione (GSH) contents in liver as well as lungs of exposed animals. In both organs phase I and phase II drug metabolizing enzymes have been found to be increased along with decrease in GSH contents following TCE inhalation. Pulmonary as well as hepatic MFO's seem to be activated by inhaled TCE probably in an attempt for its rapid detoxification and reduced glutathione is used during its biotransformation.

Ethanol prevents from acetaminophen inducible hepatic necrosis by inhibiting its metabolic activation in mice

Concomitant administration of a single acute dose of ethanol (4 g/kg) protected mice from the hepatocellular injury observed upon administration of a large dose of acetaminophen (400 mg/kg). This was evidenced by the normal histological appearances of liver sections and by the lowered serum aminotransferase activities in mice treated with ethanol and acetaminophen together. In the mice treated with acetaminophen alone, along with the hepatic necrosis, the hepatic microsomal aminopyrine N-demethylase activity was decreased. However, co-administration of ethanol prevented this acetaminophen dependent inhibition on the microsomal mixed function oxidase activity. Pharmacokinetic studies indicated that the concentration of un-metabolized drug in the blood was increased in the ethanol treated mice. Furthermore, upon co-administration of ethanol, although the biliary levels of acetaminophen metabolites (glucuronide, sulfate and cysteine conjugates) were decreased, the level of unmetabolized acetaminophen was increased. Our findings suggest that co-administration of an acute dose of ethanol reduces the degree of hepatocellular necrosis produced by a large dose of acetaminophen and this ethanol dependent protection is, in major part, afforded by suppression of the hepatic microsomal mixed function oxidase activity catalyzing the metabolic activation of acetaminophen.

Effects of Ischemia/Reperfusion on Hepatic Secretion and Microsomal Drug- Metabolism in rat

Ischemia causes tissue necrosis in a wide variety of pathologic conditions. Permanent deprivation of blood flow is lethal to any tissue and the prudent therapy for ischemia unquestionably is reperfusion. While reperfusion is necessary to reverse the progression towards ischemic death, reperfusion is also thought to be accompanied by its own component of injury. Oxygen free radicals, formed during ischemia/reperfusion, have been proposed as one of the main causes of reperfusion injury. Free radical attacks on biological membrane, such as mitochondria and endoplasmic reticulum, and can lead to the oxidative destruction of the polyunsaturated fatty acids of the membranes through lipid peroxidation. However, direct association between microsomal lipid peroxidation in vivo after ischemia/reperfusion and changes in secretory function and drug metabolism on the liver have not been established. Therefore, present study was performed to evaluate the hepatic secretory function and the hepatic microsomal drug metabolizing enzyme activity after ischemia/reperfusion preparation in rat liver. Further, the effect of oxygen free radical scavengers was investigated. The animals were divided into sham operation group and ischemia/reperfusion group. The ischemia/reperfusion group was subdivided into non-treated control and treated (with superoxide dismutase, allopurinol, alpha-tocopherol, deferoxamine) groups. Hepatic ischemia was produced by clamping the left branches of portal vein and hepatic artery, resulting in complete ischemia to the median and left lobes while the right lobes remained per Fused to prevent intestinal congestion. Reperfusion was permitted by declamping after 1 hour. After 1 or 5 hours of reperfusion, bile was collected, blood was obtained from abdominal aorta, and liver microsomes were isolated. The results are as follows. Serum aminotransferase was increased 15~20 times by ischemia/reperfusion. However, this increase was attenuated by free radical scavengers, especially 5 hours of reperfusion. The wet weight-to-dry weight ratio of the liver was significantly increased by ischemia/reperfusion. alpha-tocopherol pretreatment minimized the increase of ratio. Malondialdehyde level in the liver microsomal fraction was significantly increased after ischemia/reperfusion, but this increase was attenuated by scavenger pretreatment, especially alpha-tocopherol. Bile flow and cholate output but not the bilirubin output, were decreased after ischemia/reperfusion. The free radical scavenger pretreahnent restored the secretion significantly. Cytochrome P-450 content was significantly decreased after ischemia/reperfusion and ameliorated by free radical scavenger pretreatment. NADPH cytochrome P-450 reductase activity and aminopyrine N-demethylase activity were also decreased and improved by free radical scavengers pretreatment. These results indicate that ischemia/reperfusion deteriorates the hepatic secretory function as well as hepatic microsomal drug metabolizing enzyme activity, and the oxygen free radical scavengers attenuate the functional changes of the liver induced by ischemia/reperfusion.

Pasaje del antichagásico Benznidazol vía leche materna a ratas lactantes: efectos sobre el metabolismo de xenobióticos / Passage of Benznidazol antichagasics ingestion maternal milk to neonatal rats: effects on xenobiotic metabolism

El antichagásico Benznidazol presenta efectos tóxicos indeseables en su empleo clínico. Esta droga es capaz de pasar al lactante vía leche materna modificando su capacidad metabolizante de xenobióticos. En ratas lactantes cuyas madres fueron tratadas previamente con la droga el tiempo de sueño producido por pentobarbital fue modificado, así como también la actividad de la aminopirina demetilasa, que fue significativamente menor que en ratas lactantes control.

Aminopyrine-N-demethylase activity of rat liver after administration of crude cannabis extract.

The effect of cannabis extract, on the hepatic aminopyrine-N-demethylase activity was studied in rats. Daily administration of cannabis extract for 15 consecutive days increased the aminopyrine-N-demethylase activity which was significant on day 15 post-treatment at 2 and 10 mg/kg doses. At 20 mg/kg, a significant increase was observed from day 7 which continued up to day 15. These findings suggest that cannabis extract can induce hepatic aminopyrine-N-demethylase activity.

Effect of protein-calorie malnutrition on drug metabolising enzymes in rat liver.

Drugs are chiefly metabolised in the liver usually in two phases, viz. oxidation and conjugation. The present study was undertaken to investigate the effect of protein-calorie malnutrition (PCM), rehabilitation and effect of phenobarbitone on the hepatic drug metabolising enzymes in weanling albino rats, fed on a semisynthetic diet containing 18% or 0.5% protein. The two representative enzymes of oxidation and conjugation employed were aminopyrine N-demethylase and bilirubin UDP-glucuronyl transferase, respectively. The study revealed that PCM severely impairs oxidative drug metabolising enzyme but less so in conjugation stage. On refeeding 18% protein diet, drug metabolising enzymes returned to normal within 2-3 weeks. Phenobarbitone administration increased the activities of drug metabolising enzymes.