• Archives of Pharmacal Research
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• 제27권7호
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• pp.693-712
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• 2004

The rats with protein-calorie malnutrition (PCM, 5％ casein diet for a period of 4-week) were reported to exhibit 60 and 80％ suppression in the hepatic microsomal cytochrome P450 (CYP) 1 A2 and CYP2C11 levels, respectively, and 40-50％ decreases in CYP2E1 and CYP3A 1/2 levels compared to control (23％ casein diet for a period of 4-week) based on Western blot analysis. In addition, Northern blot analysis showed that CYP1 A2, CYP2E1, CYP2C11, and CYP3A1/2 mRNAs decreased in the state of PCM as well. Hence, pharmacokinetic changes of the drugs in rats with PCM [especially the area under the plasma concentration-time curve from time zero to time infinity (AUC) changes of metabolite(s)] reported from literatures were tried to explain in terms of CYP isozyme changes in the rats. Otherwise, the time-averaged nonrenal clearance ($CL_{NR}$) of parent drug was compared. Pharmacokinetic changes of the drugs in other types of malnutritional state, such as kwashiorkor and marasmus, in both human and animal models were also compared. The drugs reviewed are as follows： diuretics, antibiotics, anticancer agents, antiepileptics, antiarrythmics, analgesics, xanthines, antimalarials, and miscellaneous.

• Molecular & Cellular Toxicology
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• 제2권4호
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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.

• Journal of Pharmaceutical Investigation
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• 제41권3호
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• pp.143-146
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• 2011

Scutellariae Radix is widely used in the traditional herbal medicine for the treatment of fever, cough, dysentery, hepatitis and hypertension in Korea, China and Japan. In this study, we investigated the effects of 70% ethanolic extract of Scutellariae Radix (SRE) on CYP450-mediated drug metabolism in the in vitro systems using human liver microsomes and hepatocytes. The microsomal incubation assay showed that SRE inhibited the drug metabolism reactions catalyzed by CYP1A2, CYP2C8 and CYP2C9 in a dose-dependent manner. In particular, SRE was shown to strongly inhibit the metabolic activity of CYP1A2 with an $IC_{50}$ value of 4.6 ${\mu}g/mL$. When SRE was evaluated for its effect on the induction of CYP450 enzyme activities in cryopreserved human hepatocytes, SRE did not exhibit any effect.

• Journal of Microbiology and Biotechnology
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• 제33권3호
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• pp.378-386
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• 2023

The CYP707A family genes encoding ABA 8'-hydroxylase catabolize abscisic acid (ABA), a plant stress hormone that plays an important role in stress condition, such as drought, heat, cold and salinity. Phaseic acid (PA) is a catabolic product of ABA. Recent studies have shown that PA is important for the physiological functions in plants. It is also a neuroprotective molecule that protects against ischemic brain injury in mice. To obtain enzymes for the PA production, four CaCYP707A genes (CaCYP707A1, CaCYP707A2, CaCYP707A3 and CaCYP707A4) were isolated from hot pepper. They were heterologously expressed in Escherichia coli. Among them, CaCYP707A2 showed significantly higher expression levels in both the membrane fraction and the soluble fraction. Preferred redox partners were investigated to improve the efficiency of CaCYP707A2's catalytic reaction, and NADPH-cytochrome P450 reductase (CPR) from hot pepper (CaCPR) was preferred over other redox partners (i.e., rat CPR and ferredoxin reductase/ferredoxin). The production of 8'-hydroxy ABA and PA by ABA hydroxylation activity was confirmed in CaCYP707A2 from both membrane and soluble fractions. Therefore, CaCYP707A2 is the first identified plant CYP protein that is expressed a soluble form in cytosolic fraction having stable activity. Taken together, we propose a new CYP707A protein with industrial applications for PA production without additional modifications in E. coli heterologous expression.

• 한국임상약학회지
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• 제15권1호
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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.

• 한국환경성돌연변이발암원학회지
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• 제26권3호
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• pp.86-88
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• 2006

Cytochrome P450 1A2 (CYP1A2) is a xenobiotic metabolizing enzyme that is tissue-specifically expressed in the mammalian liver. In this study, the extent of CYP1A2 promoter methylation was analyzed to determine its potential role in the regulation of CYP1A2 in diethylnitrosamine (DEN)-induced mouse liver tumors. CYP1A2 mRNA was under-expressed about three fold in DEN-induced liver tumors compared to age-matched control livers. The CYP1A2 promoter was hypermethylated in DEN-induced liver tumors compared to controls, especially in a promoter domain close to the coding region. These results suggest that promoter methylation is involved in the regulation of CYP1A2 in mouse liver tumors.

• Molecules and Cells
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• 제25권2호
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• pp.231-241
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• 2008

Indole glucosinolates (IG) play important roles in plant defense, plant-insect interactions, and stress responses in plants. In an attempt to metabolically engineer the IG pathway flux in Chinese cabbage, three important Arabidopsis cDNAs, CYP79B2, CYP79B3, and CYP83B1, were introduced into Chinese cabbage by Agrobacterium-mediated transformation. Overexpression of CYP79B3 or CYP83B1 did not affect IG accumulation levels, and overexpression of CYP79B2 or CYP79B3 prevented the transformed callus from being regenerated, displaying the phenotype of indole-3-acetic acid (IAA) overproduction. However, when CYP83B1 was overexpressed together with CYP79B2 and/or CYP79B3, the transformed calli were regenerated into whole plants that accumulated higher levels of glucobrassicin, 4-hydroxy glucobrassicin, and 4-methoxy glucobrassicin than wild-type controls. This result suggests that the flux in Chinese cabbage is predominantly channeled into IAA biosynthesis so that coordinate expression of the two consecutive enzymes is needed to divert the flux into IG biosynthesis. With regard to IG accumulation, overexpression of all three cDNAs was no better than overexpression of the two cDNAs. The content of neoglucobrassicin remained unchanged in all transgenic plants. Although glucobrassicin was most directly affected by overexpression of the transgenes, elevated levels of the parent IG, glucobrassicin, were not always accompanied by increases in 4-hydroxy and 4-methoxy glucobrassicin. However, one transgenic line producing about 8-fold increased glucobrassicin also accumulated at least 2.5 fold more 4-hydroxy and 4-methoxy glucobrassicin. This implies that a large glucobrassicin pool exceeding some threshold level drives the flux into the side chain modification pathway. Aliphatic glucosinolate content was not affected in any of the transgenic plants.

• BMB Reports
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• 제49권3호
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• pp.173-178
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• 2016

Liver cells experience hypoxic stress when drug-metabolizing enzymes excessively consume O₂ for hydroxylation. Hypoxic stress changes the transcription of several genes by activating a heterodimeric transcription factor called hypoxia-inducible factor-1α/β (HIF-1α/β). We found that hypoxic stress (0.1% O₂) decreased the expression of cytochrome P450 7A1 (CYP7A1), a rate-limiting enzyme involved in bile acid biosynthesis. Chenodeoxycholic acid (CDCA), a major component of bile acids, represses CYP7A1 by activating a transcriptional repressor named small heterodimer partner (SHP). We observed that hypoxia decreased the levels of both CDCA and SHP, suggesting that hypoxia repressed CYP7A1 without inducing SHP. The finding that overexpression of HIF-1α increased the activity of the CYP7A1 promoter suggested that hypoxia decreased the expression of CYP7A1 in a HIF-1-independent manner. Thus, the results of this study suggested that hypoxia decreased the activity of CYP7A1 by limiting its substrate O₂, and by decreasing the transcription of CYP7A1.

• The Korean Journal of Physiology and Pharmacology
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• 제17권6호
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• pp.479-484
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• 2013

Given the CYP3A4 and CYP3A5's impact on the efficacy of drugs, the genetic backgrounds of individuals and populations are regarded as an important factor to be considered in the prescription of personalized medicine. However, genetic studies with Korean population are relatively scarce compared to those with other populations. In this study, we aimed to identify CYP3A4/5 polymorphisms and compare the genotype distributions among five ethnicities. To identify CYP3A4/5 SNPs, we first performed direct sequencing with 288 DNA samples which consisted of 96 Koreans, 48 European-Americans, 48 African-Americans, 48 Han Chinese, and 48 Japanese. The direct sequencing identified 15 novel SNPs, as well as 42 known polymorphisms. We defined the genotype distributions, and compared the allele frequencies among five ethnicities. The results showed that minor allele frequencies of Korean population were similar with those of the Japanese and Han Chinese populations, whereas there were distinct differences from European-Americans or African-Americans. Among the pharmacogenetic markers, frequencies of $CYP3A4^*1B$ (rs2740574) and $CYP3A5^*3C$ (rs776742) in Asian groups were different from those in other populations. In addition, minor allele frequency of $CYP3A4^*18$ (rs28371759) was the highest in Korean population. Additional in silico analysis predicted that two novel non-synonymous SNPs in CYP3A5 (+27256C>T, P389S and +31546T>G, I488S) could alter protein structure. The frequency distributions of the identified polymorphisms in the present study may contribute to the expansion of pharmacogenetic knowledge.

• 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.