• Korean Journal of Clinical Pharmacy
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• v.17 no.1
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• pp.13-18
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• 2007

The purpose of the present study was to investigate the effect of cimetidine on theophylline pharmacokinetics in Korean healthy normal subjects. Eight subjects were enrolled and open label, two period cross-over study was conducted without significant drug related adverse reactions. Cimetidine seemed that significantly inhibited the metabolism of theophylline, oral clearance decreased significantly when cimetidine was coadministered. Coadministered cimetidine increased $AUC_t$ and $C_{max}$ of theophylline. All subjects were genotyped using PCR-RFLP methods to evaluate the differences in metabolic capacity in accordance with CYP1A2 genotypes, but no mutant genotype was found. This suggests that metabolic capacities were not significantly affected by CYP1A2 genotypes among subjects. In conclusion, disposition of theophylline was significantly affected by coadministered cimetidine. Further evaluation with well-designed drug interaction study in accordance with various genotype of CYP1A2 is needed.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.7
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• pp.3335-3340
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• 2016

Background: Oral submucous fibrosis (OSF) is a precancerous condition with a 4 to13% malignant transformation rate. Related to the habit of areca nut chewing it is mainly prevalent in South-east Asian countries where the habit of betel quid chewing is frequently practised. On chewing, alkaloids and polyphenols are released which undergo nitrosation and give rise to N-nitrosamines which are cytotoxic agents. CYP450 is a microsomal enzyme group which metabolizes various endogenous and exogenous chemicals including those released by areca nut chewing. CYP1A1 plays a central role in metabolic activation of these xenobiotics, whereas CYP2E1 metabolizes nitrosamines and tannins. Polymorphisms in genes that code for these enzymes may alter their expression or function and may therefore affect an individuals susceptibility regarding OSF and oral cancer. The present study was therefore undertaken to investigate the association of polymorphisms in CYP1A1 m2 and CYP2E1 (RsaI/PstI) sites with risk of OSF among areca nut chewers in the Northern India population. A total of 95 histopathologically confirmed cases of OSF with history of areca nut chewing not less than 1 year and 80, age and sex matched controls without any clinical signs and symptoms of OSF with areca nut chewing habit not less than 1 year were enrolled. DNA was extracted from peripheral blood samples and polymorphisms were analyzed by PCR-RFLP method. Gene polymorphism of CYP1A1 at NcoI site was observed to be significantly higher (p = 0.016) in cases of OSF when compared to controls. Association of CYP1A1 gene polymorphism at NcoI site and the risk of OSF (Odd's Ratio = 2.275) was also observed to be significant. However, no such association was observed for the CYP2E1 gene polymorphism (Odd's Ratio = 0.815). Our results suggest that the CYP1A1 gene polymorphism at the NcoI site confers an increased risk for OSF.

• International Journal of Oral Biology
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• v.31 no.3
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• pp.107-112
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• 2006

Aldehyde dehydrogenase (ALDH) plays an important role in alcohol metabolism; ALDH is responsible for the oxidation of acetaldehyde generated during alcohol oxidation. ALDH is also known to oxidize various other endogenous and exogenous aldehydes. Cytochrome P-450 2E1 (CYP2E1), a liver microsomal enzyme, also metabolizes acetaldehyde and ethanol and can be induced by other inducers including acetone and ethanol. We examined single nucleotide polymorphisms (SNP) of ALDH and CYP2E1 genotypes in Korean. Restriction fragment length polymorphism (RFLP) method was used to determine ALDH and CYP2E1 SNP. Mutation in ALDH was 60% (heterozygote 46.7% and homozygote 13.3%) among 15 cases. CYP2E1 mutation was 52.7% (heterozygote 47.4% and homozygote 5.3%) among 19 cases.

• Korean Journal of Pharmacognosy
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• v.34 no.1 s.132
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• pp.86-90
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• 2003

For the determination of inhibiting cytochrome P450(CYP)3A4 activity, an improvement HPLC method was established by using a new internal standard and solvent system. Moreover, CYP3A4 amount for a optimum reaction of enzyme was determined by a comparative study with a variety concentration of enzyme. Using a established method, inhibitory effect of CYP3A4 that is drug metabolizing enzyme Investigated on EtOAc extracts of 5-class spices. As a result of experiment, EtOAc extract of white pepper (Piper nigrum L.) showed strong inhibitory activity. On a continuous experiment, the fraction 2, 4 and 5 of while pepper extract showed remarkable inhibitory activity. Pipeline, a main constituent of pepper was not included in these fraction. It is suggested that major compounds for the inhibitory activity of white pepper may be other ingredient that is not piperine.

• Molecular & Cellular Toxicology
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• v.2 no.4
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• pp.262-265
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• 2006

We report a case of phenytoin toxicity due to impaired drug metabolism in a patient homozygous for $CYP2C9^{\ast}3$. A 46-year-old woman was taking phenytoin to prevent postoperative seizures. She attained high serum phenytoin levels at the standard doses (300 mg/day) and developed symptoms of phenytoin toxicity including blurred vision, nausea and headache. The patient was treated with reduced doses of phenytoin and then phenytoin therapy was finally discontinued. Genotyping for CYP2C9 revealed that this patient had a homozygous genotype, $CYP2C9^{\ast}3/^{\ast}3$. This is the first Korean case of phenytoin toxicity with homozygous $CYP2C9^{\ast}3$. This case suggests the clinical usefulness of pharmacogenetic testing for individualized dosage adjustments of phenytoin.

• Bulletin of the Korean Chemical Society
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• v.35 no.1
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• pp.83-86
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• 2014

Poly(A) polymerase (PAP) play an essential role for maturation of mRNA by adding the adenylate residues at the 3' end. PAP functions are regulated through protein-protein interaction at its C-terminal region. In this study, cyclophilin A (CypA), a member of the peptidyl-prolyl cis-trans isomerase family, was identified as a partner protein interacting with the C-terminal region PAP. The interaction between PAP and CypA was inhibited by the immunosuppressive drug cyclosporine A. Deletion analysis revealed that the N-terminal 56 residues of CypA are sufficient for the interaction with PAP. Interestingly, we observed that PAP and CypA colocalize in the nucleus during SDF-1-induced chemotaxis, implying that CypA could be involved in the regulation of polyadenylation by PAP in the chemotactic cells.

• Korean Journal of Pharmacognosy
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• v.50 no.3
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• pp.159-164
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• 2019

Zanthoxylum Peel is widely used as a common spice for a variety of foods. In the orient, it has also been used as traditional agents for treating diseases such as indigestion. Recently, Zanthoxylum Peel has been reported to have anti-cancer activity, anti-microbial activity, and anti-inflammatory activity. Chemical components are known sanshool compounds and xanthoxylin. In this study, we were carried out to investigate the constituents of inhibiting a drug metabolizing enzyme CYP3A4 from Zanthoxylum Peel. CYP3A4 is known as an enzyme involved in drug metabolism as monooxygenase containing the heme. As a result of experiment, we found that bergapten ($IC_{50}=18.21{\mu}M$) and quercetin ($IC_{50}=17.27{\mu}M$) isolated from EtOAc extract of Zanthoxylum Peel showed remarkable CYP3A4-inhibiting activities. Structures of the isolated active compounds were established by chemical and spectroscopic means.

• Korean Journal of Clinical Pharmacy
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• v.15 no.1
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• pp.1-8
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• 2005

Clopidogrel is used to reduce the risk of cardiovascular events in patients with atherosclerosis documented by recent ischemic stroke, recent myocardial infarction (MI), or established peripheral arterial disease (secondary prevention). Clopidogrel is metabolized by CYP3A4, and the active metabolites inhibit platelet aggregation. The purpose of this study was to assess clopidogrel only versus clopidogrel + others (aspirin, CYP3A4 inhibitor, and CYPBA4 inducer) in terms of cardiovasculalr events and bleeding complications. We reviewed the charts of patients who visited between August 1, 2002 and August 31, 2003, retrospectively. Total 72 patients were included and they consisted of 5 groups; clopidogrel group (n=36), clopidogrel + aspirin group (n=11), clopidogrel + CYP3A4 inhibitor group (n=15), clopidogrel + aspirin + CYP3A4 inhibitor group (n=6), clopidorel + CYP3A4 inducer group (n=4). The primary endpoints at 6 months, 12 months were the composite of cardiovascular (CV) events. The secondary end-point was the incidence of bleeding events at 6months, and 12months. At 12months, the primary endpoint was not significantly different among the five groups (p=0.056). In comparison of two groups as clopidogrel only versus clopidogrel + others (aspirin, CYP3A4 inhibitor and CYP3A4 inducer), the primary endpoint was significantly different (p=0.02). The CV events were increased in the clopidogrel + others group. The secondary end point was not significantly different among the five groups (p=0.52). However, time to bleeding events was 230.8 in the clopidogrel group and 74.7 in the clopidogrel + others group (p = 0.046). In conclusion, clopidogrel interaction with aspirin, CYP3A4 inhibitor, and CYP3A4 inducer affected cardiovascular events and bleeding events. Drug interaction of clopidogrel with concurrent medications should be considered cautiously.

• Environmental Mutagens and Carcinogens
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• v.23 no.1
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• pp.30-34
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• 2003

Recent industrial society has human widely exposed to PAHs (polynuclear aromatic hydrocarbons) that are comming from the incomplete combustion of organic material as wider spread environmental contaminants. Biological activities of PAHs are not known although PAHs are considered as carcinogens. Our laboratory have been studied the effect of PAHs in the mouse liver hepa 1 cells. In this study, we examined the mouse liver hepa-l cells as a new bioassay system to evaluate bioactivity of PAHs. We have selected 13 PAHs to examine bioassay using cyp1a1-luciferase reporter gene expression system where cyp1a1 1.6 Kb 5flanking region DNA was cloned in front of luciferase reporter gene and this plasmid was transfected into hepa 1 cells transiently. This cells then used for the study to observe the effect of PAHs. We demonstrated that PAHs induced the CYP1A1 promoter and 7-ethoxyresolufin O-deethylase (EROD) activities in a concentration-dependant manner. Some of PAHs showed stronger stimulatory effect on CYP1 gene expression than TCDD. Acenaphthene, anthracene, fluorine, naphthalene, pyrene, phenanthrene, carbazole were weak responders to cyp1a1 promoter activity stimulation and EROD induction in hepa 1 cells and these chemicals seemed to respond less to EROD than cyp1a1 promoter activity. Benz(a)anthracene, benzo(b)fluoranthene, benzo(k)fluoranthene, chrysene, and dibenzo(a,h)anthracene showed strong response to cyp1a1 promoter activity stimulation and also EROD induction in hepa 1cells. Results of dose response study suggested that four strong responding PAHs, such as benzo(a)anthracene benzo(k)fluoranthene, chrysene, and dibenzo(a, h)anthracene might be mediated through arylhydrocarbon receptor system in hepa1 cells.

• Journal of Microbiology and Biotechnology
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• v.28 no.3
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• pp.439-447
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• 2018

The aromatic compound p-hydroxybenzoate (PHBA) is an important material with multiple applications, including as a building block of liquid crystal polymers in chemical industries. The cytochrome P450 (CYP) enzymes are beneficial monooxygenases for the synthesis of chemicals, and CYP53A15 from fungus Cochliobolus lunatus is capable of executing the hydroxylation from benzoate to PHBA. Here, we constructed a system for the bioconversion of benzoate to PHBA in Escherichia coli cells coexpressing CYP53A15 and human NADPH-P450 oxidoreductase (CPR) genes as a redox partner. For suitable coexpression of CYP53A15 and CPR, we originally constructed five plasmids in which we replaced the N-terminal transmembrane region of CYP53A15 with a portion of the N-terminus of various mammalian P450s. PHBA productivity was the greatest when CYP53A15 expression was induced at $20^{\circ}C$ in $2{\times}YT$ medium in host E. coli strain ${\Delta}gcvR$ transformed with an N-terminal transmembrane region of rabbit CYP2C3. By optimizing each reaction condition (reaction temperature, substrate concentration, reaction time, and E. coli cell concentration), we achieved 90% whole-cell conversion of benzoate. Our data demonstrate that the described novel E. coli bioconversion system is a more efficient tool for PHBA production from benzoate than the previously described yeast system.