• 대한수의학회지
• /
• 제44권4호
• /
• pp.507-513
• /
• 2004

Aflatoxins are produced mainly by Aspergillus flavus and Aspergillus parasiticus that grow in improperly stored cereals. Aflatoxin B1 ($AFB_1$) is a potent hepatocarcinogen in a variety of experimental animals including human beings. In spite of a high attention to the hepatocarcinogenecity of $AFB_1$, the relative toxicity of aflatoxins ($AFB_2$ and $AFG_1$) is not fully clarified. Sprague-Dawley male rats were orally administered with $AFB_1$, $AFB_2$, and $AFG_1$ at the dose of 250 ${\mu}g/kg$ (additionally including a dose of $1250{\mu}g/kg $ for $AFB_1$) body weight. Animals were then killed at 12, 24 or 48 hrs following aflatoxin exposure. Subsequently the immunohistochemical examination of p53, cytochrome p450 1A1 (CYP450 1A1), and glutathione-S-transferase placental form (GST-P) were performed. The level of the 8-OxodG in the liver was determined. Expressions of CYP450 1A1 and p53 were high in the liver of rats through 48 hrs after treatment of $AFB_1$ at the single dose of $250{\mu}g/kg $. This pattern was more clear as increasing doses. The treatment of $AFB_2$ and $AFG_1$ did not affect the expression of CYP450 1A1 but it caused weak expression of p53. The activity of GST were not found in the liver of rats treated with aflatoxins. The formation of 8-OxodG by $AFB_1$ increased in a dose-dependent manner up to 24 hrs after a single treatment of $AFB_1$ thereafter decreased to the level of control. The treatment of $AFB_2$ and $AFG_1$ did not affect the levels of 8-OxodG in the liver of rats with increasing time. These results in the present study indicate that $AFB_1$ among aflatoxins with low comparable levels is the most toxic as determined by early biomarkers such as CYP450 1A1, p53, GST-P, and 8-OxodG.

• Biomolecules & Therapeutics
• /
• 제18권4호
• /
• pp.469-476
• /
• 2010

This study was to investigate the effect of apigenin on the bioavailability of paclitaxel after oral and intravenous administration in rats. The effect of apigenin on P-glycoprotein (P-gp), cytochrome P450 (CYP)3A4 activity was evaluated. The pharmacokinetic parameters of paclitaxel were determined in rats after oral (40 mg/kg) or intravenous (5 mg/kg) administration of paclitaxel with apigenin (0.4, 2 and 8 mg/kg) to rats. Apigenin inhibited CYP3A4 activity with 50% inhibition concentration ($IC_{50}$) of 1.8 ${\mu}M$. In addition, apigenin significantly inhibited P-gp activity. Compared to the control group, apigenin significantly increased the area under the plasma concentration-time curve (AUC, p<0.05 by 2 mg/kg, 59.0% higher; p<0.01 by 8 mg/kg, 87% higher) of oral paclitaxel. Apigenin also significantly (p<0.05 by 2 mg/kg, 37.2% higher; p<0.01 by 8 mg/kg, 59.3% higher) increased the peak plasma concentration ($C_{max}$) of oral paclitaxel. Apigenin significantly increased the terminal half-life ($t_{1/2}$, p<0.05 by 8 mg/kg, 34.5%) of oral paclitaxel. Consequently, the absolute bioavailability (A.B.) of paclitaxel was significantly (p<0.05 by 2 mg/kg, p<0.01 by 8 mg/kg) increased by apigenin compared to that in the control group, and the relative bioavailability (R.B.) of oral paclitaxel was increased by 1.14- to 1.87-fold. The pharmacokinetics of intravenous paclitaxel were not affected by the concurrent use of apigenin in contrast to the oral administration of paclitaxel. Accordingly, the enhanced oral bioavailability by apigenin may be mainly due to increased intestinal absorption caused via P-gp inhibition by apigenin rather than to reduced renal and hepatic elimination of paclitaxel. The increase in the oral bioavailability might be mainly attributed to enhanced absorption in the gastrointestinal tract via the inhibition of P-gp and reduced first-pass metabolism of paclitaxel via the inhibition of the CYP3A subfamily in the small intestine and/or in the liver by apigenin. It appears that the development of oral paclitaxel preparations as a combination therapy is possible, which will be more convenient than the i.v. dosage form.

• Preventive Nutrition and Food Science
• /
• 제1권2호
• /
• pp.227-229
• /
• 1996

The effects of phenthyl isothiocyanate(PEIFTC) on xenobiotic metabolizing enzymes and cell kinetics in the target organs for Ν-nirtosobis(2-oxopropyl) amine(BOP)-tumorigenicity were investigated in female Syrian golden hamsters in order to gain the mechanistic insigths into the chemopreventive action of PEITS against BOP-initiated lung and pancreatic carcinogenesis in hamsters. Hamsters were given BOP subcuteneo-usly(s.c.) and/or PEITC by gavage 2h prior to the BOP treatment. Eight and 24h after the PEITC administration, animals were sacrificed for analyzing P450 isoenzymes, glutathine(GSH), glutathione S-transferase(GST) and cell kinetics. The PEITC pretreatment significantly reduced the hepatic P450 isoenzume levels such as CYP2B1 and DYP1A1 which were significantly increased by the BOP treatment. However, PEITC did not affect the CYP levels in the pancreas and lung. Interestingly, the PEITC pretreatment rather lowered the heparic GST and GSH levels, regradless of BOP administration. Proliferating cell nuclear antigen(PCNA)- labeling indices were dose dependently decreased by PEITC in the pancreas acini and ducts, bronchioles, and renal tubules in which the cell replication was significantly affected by BOP. These results thus suggest that PEITC exerts the chemopreventive effects in hamsters by influencing xenobiotic matabolizing phase I enzymes in the liver and regulating cell kinetics in the target organs.

• Journal of Ginseng Research
• /
• 제46권6호
• /
• pp.780-789
• /
• 2022

Background: Incretin impairment, characterized by insufficient secretion of L-cell-derived glucagon-like peptide-1 (GLP-1), is a defining step of type 2 diabetes mellitus (T2DM). Ginsenoside compound K (CK) can stimulate GLP-1 secretion; however, the potential mechanism underlying this effect has not been established. Methods: CK (40 mg/kg) was administered orally to male db/db mice for 4 weeks. The body weight, oral glucose tolerance, GLP-1 secretion, gut microbiota sequencing, bile acid (BA) profiles, and BA synthesis markers of each subject were then analyzed. Moreover, TGR5 expression was evaluated by immunoblotting and immunofluorescence, and L-cell lineage markers involved in L-cell abundance were analyzed. Results: CK ameliorated obesity and impaired glucose tolerance in db/db mice by altering the gut microbiota, especially Ruminococcaceae family, and this changed microbe was positively correlated with secondary BA synthesis. Additionally, CK treatment resulted in the up-regulation of CYP7B1 and CYP27A1 and the down-regulation of CYP8B1, thereby shifting BA biosynthesis from the classical pathway to the alternative pathway. CK altered the BA pool by mainly increasing LCA and DCA. Furthermore, CK induced L-cell number expansion leading to enhanced GLP-1 release through TGR5 activation. These increases were supported by the upregulation of genes governing GLP-1 secretion and L-cell differentiation. Conclusions: The results indicate that CK improves glucose homeostasis by increasing L-cell numbers, which enhances GLP-1 release through a mechanism partially mediated by the gut microbiota-BA-TGR5 pathway. Therefore, that therapeutic attempts with CK might be useful for patients with T2DM.

• 약학회지
• /
• 제42권4호
• /
• pp.422-430
• /
• 1998

In order to study the effects of Rhei rhizoma, Ephedrae herba and Scutellariae radix on hepatic metabolism, we examined the pretreatment effect of those on the metabolism of 7-e thoxycoumarin (EC). Water extracts (1g/kg) of Rhei rhizoma, Ephedrae herba and Scutellariae radix were administered orally to rats for 7 days, respectively. Livers were then isolated and perfused with 100mcM EC for 2 hours. The metabolites of EC, 7-hydroxycoumarin, sulfate conjugate and glucuronide conjugate were measured in the perfusates. The amount of glucuronide conjugates was decreased in Rhei rhizoma pretreated rats (p<0.01), however, 7-hydroxycoumarin was increased in Ephedrae herba pretreated rats (p<0.01). We examined whether the change of enzyme activity is related to the change of cytochrome P4501A1 and P4502B1 mRNA level in the perfused rat liver, which are responsible for EC metabolism. CYP1A1 and CYP2B1 mRNA level was increased, which was was not statistically significant with rhei rhizoma nor ephedrae herba pretreatment. We also assessed the hepatotoxicity of Rhei rhizoma, Ephedrae herba and Scutellariae radix. The activities of ALT and AST were assayed at 24 hours after 7 days administration. Only the ratio of ALT over AST was increased in ephedrae herba pretreated rats (p<0.05). Lipid peroxidation was increased in Rhei rhizoma treatment (p<0.05), while histopathological examination performed after liver perfusion did not show any difference compared with vehicle treatment. These results suggest that Ephedrae herba pretreatment increases the o-deethy-lation of 7-ethoxycoumarin in rats, which may be mediated by CYP1A1 mRNA induction.

• Biomolecules & Therapeutics
• /
• 제16권3호
• /
• pp.190-196
• /
• 2008

Deoxypodophyllotoxin (DPT) is a medicinal herb product isolated from Anthriscus sylvestris. DPT possesses beneficial activities in regulating immediate-type allergic reaction and anti-inflammatory activity through the dual inhibition of cyclooxygenase-2 and 5-lipoxygenase. In the present study, the metabolism of DPT was further characterized in rat liver microsomes isolated from male Sprague Dawley rats. The metabolism of DPT was NADPH-dependent. In addition, when liver microsomes were incubated with SKF-525A, a well-known CYP inhibitor, in the presence of $\beta$-NADPH, the metabolism of DPT was significantly inhibited. Using enriched rat liver microsomes, the anticipated isoforms of cytochrome P450s (CYPs) in the metabolism of DPT were partially characterized. Phenobarbital-induced microsomes increased in the formation of metabolite M1. The metabolite M3 was only produced in the enriched microsomes isolated from dexamethasone-treated rats. The results indicated that the metabolism of DPT would be CYP-dependent and that CYP2B and CYP3A might be important in the metabolism of DPT in rats.

• Parasites, Hosts and Diseases
• /
• 제51권2호
• /
• pp.165-175
• /
• 2013

The fear that schistosomes will become resistant to praziquantel (PZQ) motivates the search for alternatives to treat schistosomiasis. The antimalarials quinine (QN) and halofantrine (HF) possess moderate antischistosomal properties. The major metabolic pathway of QN and HF is through cytochrome P450 (CYP) 3A4. Accordingly, this study investigates the effects of CYP3A4 inhibitor, ketoconazole (KTZ), on the antischistosomal potential of these quinolines against Schistosoma mansoni infection by evaluating parasitological, histopathological, and biochemical parameters. Mice were classified into 7 groups: uninfected untreated (I), infected untreated (II), infected treated orally with PZQ (1,000 mg/kg) (III), QN (400 mg/kg) (IV), KTZ (10 mg/kg)+QN as group IV (V), HF (400 mg/kg) (VI), and KTZ (as group V)+HF (as group VI) (VII). KTZ plus QN or HF produced more inhibition (P<0.05) in hepatic CYP450 (85.7% and 83.8%) and CYT b5 (75.5% and 73.5%) activities, respectively, than in groups treated with QN or HF alone. This was accompanied with more reduction in female (89.0% and 79.3%), total worms (81.4% and 70.3%), and eggs burden (hepatic; 83.8%, 66.0% and intestinal; 68%, 64.5%), respectively, and encountering the granulomatous reaction to parasite eggs trapped in the liver. QN and HF significantly (P<0.05) elevated malondialdehyde levels when used alone or with KTZ. Meanwhile, KTZ plus QN or HF restored serum levels of ALT, albumin, and reduced hepatic glutathione (KTZ+HF) to their control values. KTZ enhanced the therapeutic antischistosomal potential of QN and HF over each drug alone. Moreover, the effect of KTZ+QN was more evident than KTZ+HF.

• Archives of Pharmacal Research
• /
• 제21권1호
• /
• pp.35-40
• /
• 1998

Human cytochrome P450 4F2 shows high regioselectivity in hydroxylation of stearic acid and leukotriene $ B_4.$ As a first step of its regulation study, human cytochrome P450 4F2 genomic DNA was isolated from liver of a person who was administered clofibrate for 10 years. From Southern hybridization, restriction enzyme digestion and sequencing experiments, isolated genomic DNA fragment was found to contain around 32 Kb DNA and more than 20 Kb of $5^I$ end regulatory region. Sequences of the structural gene region revealed exon 1 and exon 2. Further regulation studies would elucidate the feedback mechanisms of the oxidative degradation of fatty acids, inflammatory response and the clearance of leukotriene B4 in the liver. Furthermore, regulation study of this gene could explain the species difference in responses to peroxisome proliferator and help in the safety evaluation of peroxisome proliferating chemicals to human being.

• Biomolecules & Therapeutics
• /
• 제24권1호
• /
• pp.40-48
• /
• 2016

The pregnane X receptor (PXR), a liver and intestine specific receptor,, has been reported to be related with the repression of inflammation as well as activation of cytochromosome P450 3A (CYP3A) expression. We examined the effect of PXR on tetrachloromethane (CCl4)-induced mouse liver inflammation in this work. Ginkgolide A, one main component of Ginkgo biloba extracts (GBE), activated PXR and enhanced PXR expression level, displayed both significant therapeutic effect and preventive effect against $CCl_4$-induced mouse hepatitis. siRNA-mediated decrease of PXR expression significantly reduced the efficacy of Ginkgolide A in treating $CCl_4$-induced inflammation in mice. Flavonoids, another important components of GBE, were shown anti-inflammatory effect in a different way from Ginkgolide A which might be independent on PXR because flavonoids significantly inhibited CYP3A11 activities in mice. The results indicated that anti-inflammatory effect of PXR might be mediated by enhancing transcription level of $I{\kappa}B{\alpha}$ through binding of $I{\kappa}B{\alpha}$. Inhibition of NF-${\kappa}B$ activity by NF-${\kappa}B$-specific suppressor $I{\kappa}B{\alpha}$ is one of the potential mechanisms of Ginkgolide A against CCl4-induced liver inflammation.

• 대한예방한의학회지
• /
• 제13권2호
• /
• pp.51-64
• /
• 2009

Objective : This research was aimed to investigate the anti-tumor effect, safety, mechanism and metabolizing enzyme of Agrimonia pilosa LEDEB(APL) in female C57B/L mouse. Methods : At first, to evaluate the anti-tumor activity of APL, we divided into four groups, normal, control, APL100(100mg/kg), APL150(150mg/kg). LLC obtained American Type Culture Collection was used. LLC had been inoculated to induce tumor. To measure the anti-tumor effect of APL, we calibrate tumor size and weight. To study for mechanism of anti-tumor in APL, we used western blotting and to know metabolizing enzyme in APL we used to real-time PCR. Results : APL100, APL150 inhibited tumor growth after medicine injected. APL did not only induced caspase-dependent apoptosis in LLC-bearing mouse tumor. In APL100, it were decreased 72% in CYP3A11. In APL150, it were decreased 62%, 75% in CYP3A11 and MRP1a respectively. Conclusion : These results suggests that APL has some anti-tumor effects in female C57B/L mouse tumor. APL should be careful use with other drugs related with CYP3A11 or MRP1a.