• Biomolecules & Therapeutics
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• v.8 no.4
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• pp.299-304
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• 2000

The modulation of cytochrome P450(P450) activities and glutathione S-transferase (GST) was investigated after i.p. administration of glucose-diethyldithiocarbamate (Glu-DDTC) to rats. P450 1 A2 and 2El activities were inhibited by 60% 4 hr after the administration of 200 mg Glu-DDTC/kg and those activities were recovered to original levels 24 hr after dosing. In contrast, GST activities were enhanced up to 24 hr after dosing. These results seem to be due to the bifunctional activity of Glu-DDTC. Glu-DDTC acts as an inhibitor of P450 enzymes as well as inducer of GST enzyme. Glu-DDTC inhibited PNP hydroxylation (P450 2El) and ethoxycoumarin O-deethylation (P450 1A2) in a dose-dependent manner up to 200 mg/kg wherease it did not affect testosterone 6$\beta$-hydroxylation (P450 3A) and pentoxyresorufin O-dealkylation (P450 2B) activities. Induction of GST activity toward 1-chloro-2,4-dinitrobenzene (CDNB) and 1,2-dichloro-4-nitrobenzenen (DCNB) was dependent on the dose of Glu-DDTC and no species difference in the GST induction was seen between rat and mouse. Amoung GST subunits, Ya, Yb1 and partially Yb2 were induced by Glu-DDTC as conjugated by western blotting. The levels Yp, Yk and Yc subunits were not affected by Glu-DDTC treatment. Therefore the enhanced activity of GST toward CDNB and DCNB might be due to the induction of Ya, Ybl and partially Yb2 subunits. In conclusion, Glu-DDTC selectively inhibited P45O 1A2 and P450 2El activities whereas it enhanced Ya, Ybl subunits and partially Yb2 subunits of GST and the antimutagenic activity of this compound might be attributed from the modulation of these enzyme activities in animals.

• Analytical Science and Technology
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• v.5 no.1
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• pp.83-90
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• 1992

The $^{14}C$-warfarin used as rodenticids was identified from various organs of sprague dawley with scintillation counter. And the cytochrome p-450 which was induced by coumarin derivatives was identified with electrophoresis. The distributions of $^{14}C$-warfarin after $14.8{\mu}Ci/kg$ oral application at each organ was as follows; urine-7.5%, blood-0.44%, feces-0.9%, liver-0.66%, lung-0.86%, kidney-0.8%, heart-0.43% and spreen-0.33% after 24hrs. The cytochrome p-450 was purified by Octyl Sepharose CL-4B hydrophobic chromatography and isozymes were 50.8 Kd in control group, 53.3 Kd and 55.2 Kd in coumarin pretreated group and 50.8 Kd, 54.6 Kd and 57.7 Kd in warfarin pretreated group.

• YAKHAK HOEJI
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• v.43 no.6
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• pp.827-833
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• 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.

• Analytical Science and Technology
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• v.8 no.2
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• pp.117-124
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• 1995

To Purify hemoproteins showing from 218nm absorbance, crude liver extract of human with hepatocirrhosis was treated with Triton N-101. Hemoproteins were purified by modification of Mohamed's method. This crude extract was applied to Octyl-Sepharose CL-4B column and the step elution was performed with 0.06% Lubrol PX and 0.25% Lubrol PX. The absorption of effluents were examined at 418nm and two peaks were appeared(Fig. 2). Hemoproteins were purified from Hyydroxyapatite and DEAE-Sephadex A-25 columns which the first peak was applied to(Fig. 3, 4). In death with suddenly, purified hemoproteins with 62 and 45kDa were obtained from 12.5% SDS-PAGE. In death with hepatocirrhosis, purified hemoprotein with 54kDa was obtainded from 12.5% SDS-PAGE(Fig. 5). Cytochrome P450 was purified to a specific content of 20.8nmol/mg protein with a recovery of about 4.1%. Absorbance maximum of these hemoproteins were 446nm at UV spectruum(Fig. 6).

• Mass Spectrometry Letters
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• v.7 no.4
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• pp.106-110
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• 2016

Ginseng, a traditional herbal drug, has been used in Eastern Asia for more than 2000 years. Various ginsenosides, which are the major bioactive components of ginseng products, have been shown to exert numerous beneficial effects on the human body when co-administered with drugs. However, this may give rise to ginsenoside-drug interactions, which is an important research consideration. In this study, acassette assay was performed the inhibitory effects of 12 ginsenosides on seven cytochrome P450 (CYP) isoforms in human liver microsomes (HLMs) using LC-MS/MS to predict the herb-drug interaction. After incubation of the 12 ginsenosides with seven cocktail CYP probes, the generated specific metabolites were quantified by LC-MS/MS to determine their activities. Ginsenoside Rb1 and F2 showed strong selective inhibitory effect on CYP2C9-catalyzed diclofenac 4'-hydroxylation and CYP2B6-catalyzed bupropion hydroxylation, respectively. Ginsenosides Rd showed weak inhibitory effect on the activities of CYP2B6, 2C9, 2C19, 2D6, 3A4, and compound K, while ginsenoside Rg3 showed weak inhibitory effects on CYP2B6. Other ginsenosides, Rc, Rf, Rg1, Rh1, Rf, and Re did not show significant inhibitory effects on the activities of the seven CYPs in HLM. Owing to the poor absorption of ginsenosides after oral administration in vivo, ginsenosides may not have significant side effects caused by interaction with other drugs.

• Mass Spectrometry Letters
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• v.12 no.4
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• pp.172-178
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• 2021

HYIpro-3-1 is an adjuvant for preventing or treating inflammatory growth diseases. In this study, we identified the metabolic pathway of HYIpro-3-1 in human liver microsomes (HLMs) by quadrupole-orbitrap high-resolution mass spectrometry (HR-MS) and characterized the major human cytochrome P450 (CYP). Ten metabolites were identified, including one O-demethylation (M1), two O-demethylation and monohydroxylation (M2 and M3), and seven monohydroxylation metabolites (M4-M10). Based on the HR-MS² spectra, the metabolites are divided into two groups of monohydroxylated metabolites according to the hydroxylation position. We verified that HYIpro-3-1 is metabolized by CYP in HLMs, CYP2B6 is mainly involved in O-demethylation, and various CYPs are involved in the monohydroxylation of HYIpro-3-1.

• YAKHAK HOEJI
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• v.28 no.1
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• pp.53-59
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• 1984

Drug-metabolizing system which has the important role in drug metabolism is localized in smooth endoplasmic reticulum of hepatocytes and is composed of NADPH, NADPH-cytochrome $P_{450}$ reductase, cytochrome $P_{450}$ and others. It is well known that the enzyme system is induced by phenobarbital and methylcholanthrene. Lipid peroxidation is reaction of oxidative deterioration of polyunsaturated lipids. Formation of lipid peroxides in liver microsome has been found to produce degradation of phospholipid, which are major components of microsomal membrane. The relationship between the formation of lipid oxides and the activities of drug-metabolizing enzyme in the liver of rats was reported by several investigators. In this study the effect of riboflavin tetrabutylate, an antioxidant on lipid peroxidation, specially the relationship between lipid peroxidation and drug-metabolizing enzyme system was investigated. In addition the effect of vitamin A derivatives, such as retinoic acid and retinoid on the enzyme was also observed. Results are summarized as followings. 1) The pretretment with riboflavin tetrabutylate inhibited completely the lengthened sleeping time due to $CCl_{4}$ treatment. 2) The increase of TBA value was prevented by the pretreatment with riboflavin tetrabutylate. 3) The pretreatment with riboflavin tetrabutylate also prevented the decrease of drug-metabolizing enzyme caused by $CCl_{4}$. 4) Both retinoic acid and retinoid remarkably decreased the activity of aminopyrine demethylase. Pretreatment of riboflavin tetrabutylate, however, prevented inhibitory effect of retinoic acid on the enzyme activity.

• Biomolecules & Therapeutics
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• v.22 no.2
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• pp.155-160
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• 2014

Thelephoric acid is an antioxidant produced by the hydrolysis of polyozellin, which is isolated from Polyozellus multiplex. In the present study, the inhibitory effects of polyozellin and thelephoric acid on 9 cytochrome P450 (CYP) family members (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) were examined in pooled human liver microsomes (HLMs) using a cocktail probe assay. Polyozellin exhibited weak inhibitory effects on the activities of all 9 CYPs examined, whereas thelephoric acid exhibited dose- and time-dependent inhibition of all 9 CYP isoforms ($IC_{50}$ values, $3.2-33.7{\mu}M$). Dixon plots of CYP inhibition indicated that thelephoric acid was a competitive inhibitor of CYP1A2 and CYP3A4. In contrast, thelephoric acid was a noncompetitive inhibitor of CYP2D6. Our findings indicate that thelephoric acid may be a novel, non-specific CYP inhibitor, suggesting that it could replace SKF-525A in inhibitory studies designed to investigate the effects of CYP enzymes on the metabolism of given compounds.

• Journal of Haehwa Medicine
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• v.8 no.1
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• pp.643-657
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• 1999

Through observing effect of BOPEASAN(BPT) on an aging white rat's metabolic enzyme system, the following conclusions were addressed 1. The quantity of the lipid peroxide in lung of was decreased meaningfully in all of experimental subject groups, relatively to counterpart groups. 2. Cytochrome P-450, Cytochrome b5, NADPH-Cytochrome P45, was decreased meaningfully in the experimental subject groups B,C and D. 3. superoxide dismutase, catarase, grutathione peroxidase, was increased meaningfully in the experimental subject groups B.C and D. 4. glutathione, glutathione S-transferase, glutathione redutase, ${\gamma}$-Glutamylcytein synthetase, had no meaningful change in the experimental subject groups. Regarding the above conclusions, the Bopeasan was affecting positively on both lipid peroxide a nd the enzyme system, as well as it has efficacy of suppressing the phenomena of aging, Therefore, the Bopeasan is, hereafter, expected to be applied clinically.

• Archives of Pharmacal Research
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• v.29 no.4
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• pp.333-338
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• 2006

The aim of this study was to investigate the effect of morin on the bioavailability of nimodipine after administering nimodipine (15 mg/kg) orally to rabbits either co-administered or pretreated with morin (2, 10 and 20 mg/kg). The plasma concentrations of nimodipine in the rabbits pretreated with morin were increased significantly (p<0.05 at 10 mg/kg, p<0.01 at 20 mg/kg) compared with the control, but the plasma concentrations of nimodipine co-administered with morin were not significant. The areas under the plasma concentration-time curve (AUC) and the peak concentrations $(C_{max})$ of the nimodipine in the rabbits pretreated with morin were significantly higher (p<0.05 at 10 mg/kg, p<0.01 at 20 mg/kg), but only the $C_{max}$ of nimodipine coadministered with morin 10 mg/kg was increased significantly (p<0.05). The absolute bioavailability $(A.B\%)$ of nimodipine in the rabbits pretreated with morin was significantly (p<0.05 at 10 mg/kg, p<0.01 at 20 mg/kg) higher $(54.1-65.0\%)$ than the control $(36.7\%)$. The increased bioavailability of nimodipine in the rabbits pretreated with morin might have been resulted from the morin, which inhibits the efflux pump P-glycoprotein and the first-pass metabolizing enzyme by cytochrome P-450 3A4 (CYP 3A4).