• Mass Spectrometry Letters
• /
• v.9 no.2
• /
• pp.61-65
• /
• 2018

KPLA-012, a benzopyranyl 1,2,3-triazole compound, is considered a potent $HIF-1{\alpha}$ inhibitor based on the chemical library screening, and is known to exhibit anti-angiogenetic and anti-tumor progressive effects. The aim of this study was to investigate the pharmacokinetic properties of KPLA-012 in ICR mice and to investigate in vitro characteristics including the intestinal absorption, distribution, metabolism, and excretion of KPLA-012. The oral bioavailability of KPLA-012 was 33.3% in mice. The pharmacokinetics of KPLA-012 changed in a metabolism-dependent manner, which was evident by the low recovery of parent KPLA-012 from urine and feces and metabolic instability in the liver microsomes. However, KPLA-012 exhibited moderate permeability in Caco-2 cells ($3.1{\times}10^{-6}cm/s$) and the metabolic stability increased in humans compared to that in mice (% remaining after 1 h; 47.4% in humans vs 14.8% in mice). Overall, the results suggest that KPLA-012 might have more effective pharmacokinetic properties in humans than in mice although further studies on its metabolism are necessary.

• Journal of Microbiology and Biotechnology
• /
• v.15 no.1
• /
• pp.183-187
• /
• 2005

Abstract The cancer chemopreventive potential of chitosanoligosaccharides was investigated by measuring the induction of quinone reductase and glutathione S-transferase activities and inhibition of cytochrome P450 1A1, 2B1, and 2E1 activities. Chitosanoligosaccharide I (1-${\kappa}$Da${\kappa}$Da) significantly induced glutathione S-transferase activity with a maximal 1.5-fold increase at 500 ${\mu}$g/ml, while chitosanoligosaccharide II (3-${\kappa}$Da${\kappa}$Da) (500 ${\mu}$g/ml) strongly induced quinone reductase (p<0.01) and glutathione S-transferase (p<0.005) activities. The in vitro incubation of rat liver microsomes with chitosanoligosaccharides I and II (2.5, 5, 50, and 500 ${\mu}$g/ml) showed a dose-dependent inhibiton of cytochrome P450 1A1, 2B1, and 2E1 activities. Chitosanoligosaccharide II was a more potent inhibitor of cytochrome P450 2B1 activity than chitosanoligosaccharide I. Accordingly, these findings suggest that chitosanoligosaccharides are potential chemopreventive agents.

• Proceedings of the Korean Society of Applied Pharmacology
• /
• 1995.04a
• /
• pp.67-67
• /
• 1995

Acyl-CoA:cholesterol acyltransferase (ACAT, EC 2.3.1.26) plays an important role in the control of intracellular free cholesterol content via its cholesterol esterifying activity. ACAT inhibitors are expected to be effective for treatment of atherosclerosis and hypercholesterolemia. In the course of a screening program for ACAT inhibitors from microbial sources, GERI-BP001 M, A, and B were isolated from the fermentation broth of a fungal strain. GERI-BP001 compounds were isolated from a culture broth of Aspergillus fumigatus F37 by acetone extraction, EtOAc extraction, SiO$_2$ column chromatography, and reverse phase HPLC. The structure of GERI-BP001 coumpounds were determined by $^1$H-NMR, $\^$l3/C-NMR, 2D-NMR, NOESY, and long range C-H COSY experiments. GERI-BP001 M, A, and B inhibit ACAT activity in an enzyme assay system using rat liver microsomes by 50% at concentrations of 75, 147, and 71 ${\mu}$M, respectively.

• Journal of Microbiology and Biotechnology
• /
• v.18 no.11
• /
• pp.1785-1788
• /
• 2008

Phenylpyropenes A, B, and C, isolated from Penicillium griseofulvum F1959, inhibited DGAT in rat liver microsomes with $IC_{50}$ values of $78.7{\pm}1.6$, $21.7{\pm}0.2$, and $11.04{\pm}0.2{\mu}M$, respectively. In addition, a kinetic analysis using a Lineweaver-Burk plot revealed that phenylpyropene C was a noncompetitive inhibitor of DGAT. The apparent Michaelis constant ($K_m$) value and inhibition constant ($K_i$) value were calculated to be $8{\mu}M$ and $10.48{\mu}M$, respectively. Moreover, phenylpyropene C inhibited triglyceride formation in HepG2 cells.

• Journal of Environmental Health Sciences
• /
• v.19 no.3
• /
• pp.58-63
• /
• 1993

In order to elucidate the alteration of drug-metabolizing enzymes and mechanism in the animal with hepatic injury and ketosis, the regulation of P450IIE was studied in the rats with heaptic injury caused by CCl$_4$ and with ketosis caused by streptozotocin and high-fat diet. P450IIE expression in liver was examined by the combination of enzyme activities, Western immunoblot, and mRNA Northern blot analyses using specific polyclonal antibody and cDNA probe for P450IIE. Enzyme activity and amounts of immunoreactive P450IIE were rapidly decreased in a time-dependent manner after a single dose of CCl$_4$ . However, the decreases in P450IIE enzyme activity and immunoreactive protein by CCl$_4$ were not accompanied by a decline in its mRNA level. The data thus suggested a post-translational reduction of P450IIE by CCl$_4$. The enzyme activities (aniline hydroxylase) in hepatic microsomes were elevated about 2-3-fold by streptozotocin and feeding with a high fat diet. This increases in enzyme activities were also accompanied by 3-fold increases in immunoreactive P450IIE protein and its mRNA. Our data thus indicated that P450IIE induction during the ketosis appears to be due to pretranslational activation.

• Archives of Pharmacal Research
• /
• v.8 no.3
• /
• pp.119-132
• /
• 1985

The apparent effectiveness of 1-naphthyl-N-methyl carbamate (carbaryl) against a wide variety of insects motivated the study of its mammalian toxicity. In this toxicological study of carbaryl, mature male rats inhaled carbaryl at a mean concentration of 112mg, 168mg and 224 mg/$m^{3}$ for one hour. After inhalation, pentobarbital sleeping time, Nadph-cytochrome c reductase activity, cytochrome p-450 and protein content in liver microsomes, various tissue residues, cholinesterase inhibition in plasma and histopathological findings at autopsy were observed. The pentobarbital sleeping time was prolonged in rats inhaled with carbaryl for one day while the sleeping time was shortened in the 3 days inhaled group. The changes of cytochrome p-450 content and NADPH-cytochrome c reductase activity exhibited biphasic response showing the decrease in the one day inhaled group and the increase in the 3 days inhaled group. The marked depression of plasma ChE activity was observed in rats inhaled with carbaryl at 112 mg/$m^{3}$, however no more progressive effect was observed at the higher concentration of the compound. The main observations in histopathological finding were ciliary detachment, epithelial swelling and subepithelial inflammatory cellular infiltration in trachea due to the irritation.

• Mass Spectrometry Letters
• /
• v.14 no.3
• /
• pp.116-119
• /
• 2023

Gynostemma pentaphyllum (Thunb.) Makino extract, a natural product with a history of traditional use, has gained attention for its potential health benefits. This study aimed to investigate its effects on key cytochrome P450 (CYP) enzymes using LC-MS/MS. Human liver microsomes and cDNA-expressed CYP2C8, CYP2C9, CYP2C19, and CYP3A4 supersomes were employed. Enzyme activity was assessed based on the formation of CYP-specific marker metabolites. The resulting data showed that the extract exhibited inhibitory effects on CYP2C8, CYP2C9, CYP2C19, and CYP3A4. Thus, G. pentaphyllum extract may influence the pharmacokinetics of drugs metabolized by CYP2C8, CYP2C9, CYP2C19, and CYP3A4. These findings emphasize the importance of considering potential herb-drug interactions when incorporating this extract into therapeutic regimens or dietary supplements.

• Journal of the Korean Society of Food Science and Nutrition
• /
• v.34 no.1
• /
• pp.21-26
• /
• 2005

Although the sesame lignans, sesamol, have been shown to possess antioxidative activity, less is known about the metabolism and antioxidative properties of sesamol, a major constituent of sesame oil. To determine the ability of sesamol to act as an antioxidant in vivo, we fed rats a diet containing 0.5% sesamol for 3 wk and studied its metabolism and its effects on oxidative stress. Body weight gain and weight of liver, kidneys were significantly higher in the rats fed sesamol than in rats fed the control diets. GST and GST-Px activities in rat liver microsomes were higher in rats fed sesamol and CAT activities were found to be significantly increased in rats fed sesamol. The formation of TBARS was decreased in the liver of rat fed the 0.5% sesamol diet than in controls. We detected sesamol metabolites in liver and kidneys of rats fed sesamol and its metabolites were present as conjugated glucuronides and sulfates. In contrast, not detected sesamol peak in other organs such as colon, small intestine and pancreas.

• Journal of Korean Society of Occupational and Environmental Hygiene
• /
• v.19 no.1
• /
• pp.73-79
• /
• 2009

This study was undertaken to investigate the effects of single and combined exposure of toluene (T) and xylene (X) on the cytochrome-450(CYP)-mediated metabolizing capacity, induction of CYP isozymes and the excretion of their metabolites in urine. Animal were adults male Sprague-Dawley (SD) rats and divided into 4 groups such as control, T (treated with 63.7 mg/body kg), X (treated with 65.9 mg/body kg) and TX(T=X). Organic solvents was administrated by intraperitoneal injection for 3 days. The contents of protein and CYP in liver microsomes of control group were $16.48{\pm}0.56 mg/m{\ell}$ and $0.744{\pm}0.025$ nmol/mg protein, respectively, and they contents were significantly lower than in derived from treated groups (p<0.01). The activities of PROD and ${\rho}NPH$ were significantly higher in single treated groups than in control and combined group (TX). When Western immunoblotting were carried out with two monoclonal antibodies (MAb 1-98-1 and MAb 2-66-3) which were specific against CYP2B1/2 and CYP2E1, respectively, a strong signal corresponding to CYP2B1/2 was observed in microsomes obtained from rats treated with X and TX. The color density against CYP2E1 was slightly increased in T and TX groups compared with C and X groups. The amounts of urinary hippuric acid in T single treated group was $3.29{\pm}1.97$ g/g creatinine and TX combined group was $2.91{\pm}1.76$ g/g creatinine, but was not significant. However, amount of urinary methy hippuric acid in X single treated group ($1.62{\pm}0.72$ g/g creatinine) was significantly higher than TX combined group ($0.93{\pm} 0.63$ g/g creatinine)(p<0.01). These results suggested that CYP2E1 isozyme might be responsible for the metabolism of T, and CYP2B1/2 isozyme is for X. And also, difference of metabolites level between single and combined group may be speculated that the intermediates of T and X interacted each other in the process of their metabolite formation reaction.

• Applied Biological Chemistry
• /
• v.46 no.3
• /
• pp.165-170
• /
• 2003

The antioxidative activity of antioxidative substances produced from several bacterial strains isolated from fermented foods were tested by $DPPH\;({\alpha},{\alpha}'-diphenyl-{\beta}-picrylhydrazyl)$ free radical scavenging activity. One of the strains showing the highest antioxidative activity was identified as Bacillus sp. based on the morphological, biochemical, physiological characteristics, and 16S rRNA sequence, and named FF-7. The most optimal medium condition for the production of antioxidative substance from Bacillus sp. FF-7 was 2% galactose as carbon source and l% tryptone as nitrogen source. The antioxidative substance produced from FF-7 in these cultural medium was also tested by in vitro experimental models, the peruxidation of linoleic acid and the peroxidation of rat tissues microsomes by using thiobarbituric acid (TBA) for assay of free malondialdehyde production. The antioxidative activity against lipid peroxidation of rat tissues microsomes was shown in the following order; brain 97.50% > heart 79.95% > kidney 77.84% > spleen 77.47% > testis 69.96% > liver 62.45%. The antioxidative substance produced from FF-7 on linoleic acid peroxidation by IBA method was effectively inhibited during four days, and 0.05% BHT (butylated hydroxytoluene) used comparative control was also effectively inhibited. Results showed that the highest antioxidative activity by DPPH method of antioxidative substance produced from Bacillus sp. FF-7 was obtained by supplementing 2% galactose as carton source and l% tryptone as nitrogen source in cultured medium, this substance effectively inhibited the formation of TBARS in brain microsome in vit개 system and in linoleic acid peroxidation.