• YAKHAK HOEJI
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• v.39 no.4
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• pp.450-460
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• 1995

The acute toxicity of fthalide in rat was studied in vivo by the observations of the changes in hematogram, serological parameters, content of cytochrome p-450, activities of NADPH-cytochrom c reductase, glucose-6-phosphatase, and the contents of cholinesterase and carboxylesterase in liver. Fthabde is a practically non-toxic substance(LD50 is 3.86g/kg), but rats were intoxicated with fthabde at a oral dose of 100 mg/kg for 12 days. WBC were significantly decreased and activities of ALT and LDH, on the cotrary, the content of glucose in serum were slightly increased. Cytochrome p-450 and lipid peroxide in liver were significantly increased in the fthalide-intoxicated rats. The longer administration of fthalide showed further increase of carboxylesterase activity in liver and serum, but decrease of activities of glucose-6-phosphatase and cholinesterase in liver and serum. These results show that fthatide can induce the hepatocellular injury and neurotoxicity.

• Proceedings of the Korean Society of Toxicology Conference
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• 2001.10a
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• pp.37-38
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• 2001

The cytochrome P450 (P450) 1 family (1A1, 1A2, 1B1) is involved in the activation of many pro-carcinogens. Previously we characterized a number of synthetic bi- and polycyclic hydrocarbon acetylenes as selective-mechanism-based inhibitors of recombinent P450s 1A1, 1A2, 1B1 (Shimada et al., Chem. Res. Toxicol., 11, 1048-1056, 1998). We reported that the drug oltipraz is a mechanism-based indicator of P450 1A2 (Lagouet et al. Chem. Res. Toxicol., 13, 245-252, 2000).(omitted)

• Archives of Pharmacal Research
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• v.18 no.6
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• pp.381-384
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• 1995

Covalent binding of the reactive metabolites of SC_42867 to microsomal proteins has been examined. In the absence of inhibitor of cytochrome oxydase (.alpha.-naphtyl-isothiocyanate) or a radical scavenger (3-terthiobuty-4-hydroxyanisol), up to 4.0% of total redioactivity used in the assay could irreversibly bind to proteins. In the presence of an inhibitor, the highest percentage of covalent binding observed is 0.7% a significant decrease of the metabolism of SC42876 was observed. These results suggest in a cytochrome P-450 dependent generation of SC_42867 metabolites significantly take part in the covalent binding process.

• Proceedings of the Korea Environmental Mutagen Society Conference
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• 2001.10b
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• pp.37-38
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• 2001

• Toxicological Research
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• v.14 no.3
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• pp.293-300
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• 1998

Previous studies have shown that the heterocycles including thiazoles are efficacious in inducing phase phase II metabolizing enzyme as well as certain cytochrome P450s and that the inductin of these matabolizing enzymes by the heterocyclic agents is highly associated with their hepatotoxicity. In the present study, the effects of benzylisothiazole (BIT), which has a isothiazole moiety, on the expression of microsomal epoxide hydrolase (mEH), major glutathione S-transerases and cytochrome P450s were studied in the rat liver in association with its hepatotoxicity. Treatment of rats with BIT(1.17 mmol/kg, 1~3d) resulted in substantial increases in the mEH. rGSTA2, rGSTA2, rGSTM1 and rGSTM2 mRNA levels, whereas rGSTA3 and rGSTA5 mRNA levels were increased to much lesser extents. A time-course study showed that the mRNA levels of mEH and rGSTs were greater at 24hr after treatment than those after 3 days of consecutive treatment. Relative changes in mEH and rGST mRNA levels were consistent with those in the proteins, as assessed by Western immunoblot analysis. Hepatic cytochrom P450 levels were monitored after BIT treatment under the assumption that metabolic activation of BIT may affect expression of the enzymes in conjunction with hepatotoxicity. Immunoblot analysis revealed that cytochrome P450 2B1/2 were 3-to 4-fold induced in rats teatd with BIT(1.17 mmol/kg/day.3days), whereas P450 1A2, 2C11 and 3A1/2 levels were decreased to 20~30% of those in unteatd rats. P450 2E1 was only slightly decreased by BIT. Thus, the levels of several cytochrome P450s were suppressed by BIT treatment. Rats treated with BIT at the dose of 1.17mmol/kg for 3 days exhibited extensive multifocal nodular necrosis with moderate to extensive diffuse liver cell degeneration. No notable toxicity was observed in the kidney. These results showed that BIT induces mEH and rGSTs in the liver with increases in the mRNA levels, whereas the agent significantly decreased major cytochrome P450s. The changes in the detoxifying enzymes might be associated with the necrotic liver after consecutive treatment.

• Korean Journal of Clinical Pharmacy
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• v.19 no.1
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• pp.32-36
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• 2009

The aim of this study was to investigate the effect of simvastatin on the pharmacokinetics of nicardipine in rats. Pharmacokinetic parameters of nicardipine were determined after an oral administration of nicardipine (12 mg/kg) to rats coadministered with simvastatin (0.3 and 1.0 mg/kg). Compared with the control (given nicardipine alone), coadministration of simvastatin (1.0 mg/kg) significantly (p<0.05) increased the area under the plasma concentration (AUC) and peak plasma concentration ($C_{max}$) of nicardipine. The relative bioavailability (RB%) of nicardipine increased from 1.19- to 1.48-fold. However there were no significant changes in $t_{max}$, and $t_{1/2}$ of nicardipine. The enhanced oral bioavailability of nicardipine might be due to an inbition of cytochrom P450 3A mediated-metabolism of nicardipine in the intestine and in the liver by simvastatin. Based on these results, the concurrent use of simvastatin significantly enhanced the oral exposure of nicardipine in rats. The dosage regimen of nicardipine should be taken into consideration for potential drug interaction when combined with simvastatin in clinics.

• Journal of Pharmaceutical Investigation
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• v.37 no.2
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• pp.107-111
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• 2007

Epigallocatechin gallate (EGCC), a flavonoid, is the main component of green tea extracts. EGCG has been reported to be an inhibitor of P-glycoprotein (P-gp) and cytochrom P450 3A(CYP3A4). This study investigated the effect of long-term administration of EGCG on the pharmacokinetics of verapamil in rats. Pharmacokinetic parameters of verapamil were determined after oral administration of verapamil (9 mg/kg) in rats pretreated with EGCG (7.5 mg/hg) for 3 and 9 days. Compared to oral control group, the presence of EGCG significantly (p<0.01) increased the area under the plasma concentration-time curve (AUC) of verapamil by 102% (coad), 83.2% (3 days) and 52.3% (9 days), and the peak concentration $(C_{max})$ by 134% (coad), 120% (3 days) and 66.1% (9 days). The absolute bioavailability (A.B.%) of verapamil was significantly (p<0.01) higher by 8.4% (coad), 7.7% (3 days), 6.4% (9 days) compared to control (4.2%), and presence of EGCG was no significant change in the terminal half-life $(t_{1/2})$ and the time to reach the peak concentration $(T_{max})$ of verapamil. Our results indicate that EGCG significantly enhanced oral bioavailability of verapamil in rats, implying that presence of EGCG could be effective to inhibit the CYP3A4-mediated metabolism and P-gp efflux of verapamil in the intestine. Drug interactions should be considered in the clinical setting when verapamil is coadministrated with EGCG or EGCG-containing dietary.

• Journal of Nutrition and Health
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• v.36 no.2
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• pp.117-124
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• 2003

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.