• Archives of Pharmacal Research
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• 제26권8호
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• pp.631-637
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• 2003

Chloroquine has been used for many decades in the prophylaxis and treatment of malaria. It is metabolized in humans through the N-dealkylation pathway, to desethylchloroquine (DCQ) and bisdesethylchloroquine (BDCQ), by cytochrome P450 (CYP). However, until recently, no data are available on the metabolic pathway of chloroquine. Therefore, the metabolic pathway of chloroquine was evaluated using human liver microsomes and cDNA-expressed CYPs. Chloroquine is mainly metabolized to DCQ, and its Eadie-Hofstee plots were biphasic, indicating the involvement of multiple enzymes, with apparent $K_m and V_{max}$ values of 0.21 mM and 1.02 nmol/min/mg protein 3.43 mM and 10.47 nmol/min/mg protein for high and low affinity components, respectively. Of the cDNA-expressing CYPs examined, CYP1A2, 2C8, 2C19, 2D6 and 3A4/5 exhibited significant DCQ formation. A study using chemical inhibitors showed only quercetin (a CYP2C8 inhibitor) and ketoconazole (a CYP3A4/5 inhibitor) inhibited the DCQ formation. In addition, the DCQ formation significantly correlated with the CYP3A4/5-catalyzed midazolam 1-hydroxylation (r=0.868) and CYP2C8-catalyzed paclitaxel 6$\alpha$-hydroxylation (r = 0.900). In conclusion, the results of the present study demonstrated that CYP2C8 and CYP3A4/5 are the major enzymes responsible for the chloroquine N-deethylation to DCQ in human liver microsomes.

• 대한약학회:학술대회논문집
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• 대한약학회 2002년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
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• pp.253.1-253.1
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• 2002

DA-8159 is a new PDEV inhibitor, synthesized by Dong-A Pharm, as an oral agent to treat male erectile dysfunction. DA-8159 and sildenafil are mainly metabolized by cytochrome P450 enzyme CYP 3A4. In this study. we compared the metabolism of DA-8159 with sildenafil in vitro and in vivo. First, we quantified the remaining gatio of original compound, DA-8159 and sidenafil., after we incubated drugs for 30 minutes with human liver microsome cytochrome P 450 3A4. (omitted)

• 동의생리병리학회지
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• 제22권1호
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• pp.82-88
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• 2008

We evaluated the potential protective activity of the traditional Korean medicinal herb, Corni fructus (CF), in an experimental model of hepatotoxicity induced by carbontetrachloride $(CCl_4)$. The CF exhibited a hepatoprotective activity against Chang cell. And The expression of cytochrome P450 2E1 (CYP2E1), measured by RT-PCR and western blot, was significantly decreased in the CF treated Chang cell. But $CCl_4$ and CF has no significant effect on 1A1 and 3A1 isoform of cytochrome P450. Based on these findings, it is suggested that hepatoprotective effects of CF possibly related to antioxidative effects and downregulation of CYP2E1 expression.

• 대한예방한의학회지
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• 제12권3호
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• pp.99-113
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• 2008

In this study, the author experimented the influence of five herbal medicines, which are Lonicera japonica Thunb, Paeonia suffruticosa Andr., Fraxinus rhynchophylla Hance, Gardenia jasminoides Ellis, Scutellaria baicalensis George which are called 'Chungyulyak(淸熱藥)' on drug metabolizing enzyme cytochrome P450 3A4 in Human Liver Microsome. Above all, the reason for this study is that herbal medicines can be assumed that herbs might have interactions with drugs, other herbs, alcohol and chemicals whether those are much better synergy effects than expected effects when the medicine was treated alone or not. As a result, we showed that all of five traditional herbal medicines had no CYP 3A4 inhibition effect on 10, 20, 30, 40, $50{\mu}g/m{\ell}$ doses in Human Liver Microsome. However, this result are mostly not enough to prove that PMT has a CYP 3A4 inhibition effect. Moreover, it is not that those rates showed that those herbal medicines have CYP 3A4 induction effect. In conclusion, the result could support that those herbal medicines are more safe than chemical drugs even if this is the basic step to prove that result. Therefore, more specific studies to support this result, which are Kinetic study, cell and animal study then finally until clinical research, are required.

• 한국환경성돌연변이발암원학회지
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• 제23권3호
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• pp.94-98
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• 2003

Quercetin and naringenin are representative flavonoids that not only exert anti estrogenic, cholesterol-lowering and antioxidant activities but also can modulate the metabolism of many xenobiotics. The activity of the specific form(s) of CYP450 is likely to be a major determinant of susceptibility to chemically induced carcinogenesis between which varies among between individuals due to different dietary habits as well as genetic characteristics. People consume cooked meat or fish together with various vegetables containing substantial amounts of quercetin and naringenin that can modify the enzyme activity of CYP1A2 to stimulate or to inhibit the mutagenic activities of HCAs. Heterocyclic amines (HCAs) produced by cooking meat products at high temperatures are promutagens that are activated by cytochrome P450 (CYP) lA2. Using a newly developed Salmonella typhimurium TA1538/1A2bc-b5 strain, we tested the effect of quercetin and naringenin on the mutagenicity of 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ). TA1538/1A2bc-b5 bears two plasmids, one expressing human CYP1A2 and NADPH-P450 reductase (NPR), and the other plasmid which expresses human cytochrome b5 (cyp b5). TA1538/1A2bc-b5 cells showed high activities of 7-ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-demethylase (MROD) associated with CYP1A2 and are very sensitive to mutagenesis induced by several HCAs. MeIQ was found to be the strongest mutagen among the HCAs tested in this system. Mutagenicity of MeIQ was enhanced 50 and 42% by quercetin at 0.1 and 1 mM, respectively, but suppressed 82% and 96% at 50 mM and 100 mM. Naringenin also increased the MeIQ-induced mutation about 37% and 22% at 0.1 and 1 mM, but suppressed it 32% and 63% at 50 mM and 100 mM concentrations, respectively, in TA 1538/1A2bc-b5 cells. Thus, they stimulated the MeIQ induced mutation at low concentrations, but strongly suppressed it at high concentrations. This biphasic effect of flavonoids was due to the stimulation or the inhibition of CYP1A2 activity in a dose-dependent manner judging by the activities of EROD or MROD in the Salmonella cells. Collectively, it is likely that the biphasic effects of quercetin and naringenin on the MeIQ-induced mutagenesis in S. typhimurium TA1538/CYP1A2bc-b5 were due to their differential modification of the CYP1A2 activity in these cells.

• Archives of Pharmacal Research
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• 제29권4호
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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).

• 한국환경성돌연변이발암원학회지
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• 제9권2호
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• pp.87-96
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• 1989

Studies on the biodisposition of beta-nicotyrine by lung and liver microsomes was examined in order to provide a better understanding of its fate in this tissue. beta-nicotyrine (100$\mu$M) was incubated with microsomes (1 mg/ml) prepared from New Zealand White rabbits. The rate of oxidation observed in lung microsomal incubations was 1.7 nmoles $\beta$-nicotyrine oxidized mg$^{-1}$ min$^{-1}$ compared with 2.7 nmoles $\beta$-nicotyrine oxidized mg$^{-1}$ min$^{-1}$ by the liver microsomal preparation. However, when these rates were expressed as a function of cytochrome P-450 content, the specific activity of the metabolic oxidation catalyzed by lung (8.3 nmoles $\beta$-nicotyrine oxidized nmole cytochrome P-450$^{-1}$ min$^{-1}$) was approxiamtely 4 times greater than liver microsomes (2.3 nmoles $\beta$-nicotyrine oxidized nmole cytochrome P-450$^{-1}$ min$^{-1}$). Isozyme studies on the oxidation of $\beta$-nicotyrine employed several methods of altering activities of specific isozymes present in pulmonary microsomes, including the use of the isozyme 2 and 6 specific inhibitor $\alpa$-methyl ABT, metabolic inhibitor(MI) complex formation. The results of this inhibition study would appear to indicate the $\beta$-nicotyrine is metabolized predominantly by pulmonary isozyme 5.

• Journal of Applied Biological Chemistry
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• 제43권1호
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• pp.49-53
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• 2000

The in vitro metabolism of a new herbicide pyribenzoxim, {benzophenone O-[2,6-bis[(4,6-dimethoxy-2-pyrimidinyl)oxy]benzoyl]oxime} was studied using rice, barnyardgrass and rat liver microsomes. No metabolism of pyribenzoxim was observed with rice and barnyardgrass microsomes though the cvtochrome P450 was active, which was evidenced by the metabolism of cinnamic acid. With rat liver microsomes, four metabolites (M1, M2, M3, and M4) were produced while parent compound decreased. M1 and M2 were from the hydrolysis reactions and NADPH-dependent metabolites were M3 and M4 (major metabolite) which were hydroxylated by cytochrome P450. They were identified as bispyribac-sodium (M1), benzophenone oxime (M2), {benzophenone O-[2,6-bis[(5-hydroxy-4,6-dimethoxy-2-pyrimidinyl)oxy]-benzoyl]oxime}(M3), and {benzophenone O-[2[(5-hydroxy-4,6-dimethoxy-2l-pyrimidinyl)6-(4,.6dimethoxy-2-pyrimidinyl)oxy]benzoyl]oxime} (M4) through LC/MS/MS analyses. Based on the results obtained metabolic map of pyribenzoxim is proposed.

• Journal of Ginseng Research
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• 제40권4호
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• pp.375-381
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• 2016

Background: We evaluated the drug interaction profile of Red Ginseng (RG) with respect to the activities of major cytochrome P450 (CYP) enzymes and the drug transporter P-glycoprotein (P-gp) in healthy Korean volunteers. Methods: This article describes an open-label, crossover study. CYP probe cocktail drugs, caffeine, losartan, dextromethorphan, omeprazole, midazolam, and fexofenadine were administered before and after RG supplementation for 2 wk. Plasma samples were collected, and tolerability was assessed. Pharmacokinetic parameters were calculated, and 90% confidence intervals (CIs) of the geometric mean ratios of the parameters were determined from logarithmically transformed data using analysis of variance after RG administration versus before RG administration. Results: Fourteen healthy male participants were evaluated, none of whom were genetically defined as poor CYP2C9, 2C19, and CYP2D6 metabolizers based on genotyping. Before and after RG administration, the geometric least-square mean metabolic ratio (90% CI) was 0.870 (0.805-0.940) for caffeine to paraxanthine (CYP1A2), 0.871 (0.800-0.947) for losartan (CYP2C9) to EXP3174, 1.027 (0.938-1.123) for omeprazole (CYP2C19) to 5-hydroxyomeprazole, 1.373 (0.864-2.180) for dextromethorphan to dextrorphan (CYP2D6), and 0.824 (0.658-1.032) for midazolam (CYP3A4) to 1-hydroxymidazolam. The geometric mean ratio of the area under the curve of the last sampling time ($AUC_{last}$) for fexofenadine (P-gp) was 0.963 (0.845-1.098). Administration of concentrated RG for 2 wk weakly inhibited CYP2C9 and CYP3A4 and weakly induced CYP2D6. However, no clinically significant drug interactions were observed between RG and CYP and P-gp probe substrates. Conclusion: RG has no relevant potential to cause CYP enzyme- or P-gp-related interactions.

• 농업과학연구
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• 제38권4호
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• pp.689-693
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• 2011

The purpose of this study was to investigate the Cytochrome P450 (CYP2A6) gene as a candidate gene for the traits related with meat fatty acid composition traits in pigs. Porcine CYP2A6 polymorphisms were detected and PCR-RFLP was performed for genotyping of Korean native pig (n=14), Landrace (n=3), Duroc (n=3), Berkshire (n=3), Yorkshire (n=8) and F2 population composed of 202 individuals from an intercross between Korean Native pig and Yorkshire. PCR primer set amplified a 612 bp fragment of CYP2A6 and digestion of the PCR products was performed with the restriction enzymes SchI. The CYP2A6 SchI polymorphism was only found in the KNP breed. The genotype frequencies of TT, TC and CC genotypes were 0.36, 0.56 and 0.08 in the KNP respectively and the other pig breeds were fixed with CC genotype (Duroc, Landrace, Berkshire and Yorkshire). Statistical association between genotypes and fatty acid composition traits were tested in the Korean native pig and Yorkshire crossed F2 pigs. The CYP2A6 SchI polymorphism was associated with only fatty acid composition C20:3n3 level (cis11,14,17-Eicosatrienoic acid, p=0.0252). The 'T' allele was associated with lower C20:3n3 level. Further study is required to validate the genotypic association and biological consequence of the CYP2A6 gene polymorphism in pigs.