• YAKHAK HOEJI
• /
• v.46 no.3
• /
• pp.179-184
• /
• 2002

The abuse of dextromethorphan has been prevalent for 15 years in Korea and its fatal cases were reported even though it has proved to be very safe. In this study, to investigate the safety and tolerance assessment of dextromethorphan, the metabolic phenotyping and genotype of dextromethorphan were studied. After a single 30 mg of dextromethorphan oral administration to 74 volunteers, concentration of dextromethorphan and its metabolites, dextrorphan, hydroxymorphinan and methoxymorphinan were measured in urine which collected during 8hrs after the drug administration. CYP2D6 phenotype was determined from the ratio of dextromethorphan to dextrorphan. GC/MS was used to quantify dextromethorphan and its metabolites. For genotyping, mutant alleles of the CYP2D6 gene were identified. 24 subjects (32.4％) were homozygous for CYP2D6＊10B, 29 subjects (39.2％) were heterozygous for this allele, while in 21 subjects (28.4％) no exon 1 mutation could be found. The frequency of CYP2D6＊10B-allele containing the 188C T mutation was 54％ of total subjects studied.

• Toxicological Research
• /
• v.9 no.2
• /
• pp.153-158
• /
• 1993

Pyridine and acetone are efficacious inducers of CYP2E1 in both rats and rabbits. The response in the elevation of CYP2E1 levels, changes in CYP2E1 mRNA levels, and enhanced translational processing of hepatic CYP2E1 mRNA during the early phase of CYP2E1 induction by the solvents pyridine and acetone were examined. Time-depen-dent incease in CYP2E1 levels occurred at early times (6-24h) following a single dose of pyridine treatmene, as assessed by Western immunoblot analysis, whereas the levels in CYP2E1 mRNA transiently decreased at 12h post-treatment, returning to the level present in untreated animals.

• Biomolecules & Therapeutics
• /
• v.23 no.5
• /
• pp.486-492
• /
• 2015

Drug metabolism mostly occurs in the liver. Cytochrome P450 (CYP) is a drug-metabolizing enzyme that is responsible for many important drug metabolism reactions. Recently, the US FDA and EU EMA have suggested that CYP enzyme induction can be measured by both enzymatic activity and mRNA expression. However, these experiments are time-consuming and their interassay variability can lead to misinterpretations of the results. To resolve these problems and establish a more powerful method to measure CYP induction, we determined CYP induction by using luminescent assay. Luminescent CYP assays link CYP enzyme activity to firefly luciferase luminescence technology. In this study, we measured the induction of CYP isozymes (1A2, 2B6, 2C9, and 3A4) in cryopreserved human hepatocytes (HMC424, 478, and 493) using a luminometer. We then examined the potential induction abilities (unknown so far) of mesalazine, a drug for colitis, and mosapride citrate, which is used as an antispasmodic drug. The results showed that mesalazine promotes CYP2B6 and 3A4 activities, while mosapride citrate promotes CYP1A2, 2B6, and 3A4 activities. Luminescent CYP assays offer rapid and safe advantages over LC-MS/MS and qRT-PCR methods. Furthermore, luminescent CYP assays decrease the interference between the optical properties of the test compound and the CYP substrates. Therefore, luminescent CYP assays are less labor intensive, rapid, and can be used as robust tools for high-throughput CYP screening during early drug discovery.

• Journal of Pharmaceutical Investigation
• /
• v.41 no.3
• /
• pp.143-146
• /
• 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.

• Korean Journal of Clinical Pharmacy
• /
• v.26 no.4
• /
• pp.312-317
• /
• 2016

Objective: Midazolam is mainly metabolized by cytochrome P450 (CYP) 3A. Inhibition or induction of CYP3A can affect the pharmacological activity of midazolam. The aims of this study were to develop a population pharmacokinetic (PK) model and evaluate the effect of CYP3A-mediated interactions among ketoconazole, rifampicin, and midazolam. Methods: Three-treatment, three-period, crossover study was conducted in 24 healthy male subjects. Each subject received 1 mg midazolam (control), 1 mg midazolam after pretreatment with 400 mg ketoconazole once daily for 4 days (CYP3A inhibition phase), and 2.5 mg midazolam after pretreatment with 600 mg rifampicin once daily for 10 days (CYP3A induction phase). The population PK analysis was performed using a nonlinear mixed effect model ($NONMEM^{(R)}$ 7.2) based on plasma midazolam concentrations. The PK model was developed, and the first-order conditional estimation with interaction was applied for the model run. A three-compartment model with first-order elimination described the PK. The influence of ketoconazole and rifampicin, CYP3A5 genotype, and demographic characteristics on PK parameters was examined. Goodness-of-fit (GOF) diagnostics and visual predictive checks, as well as bootstrap were used to evaluate the adequacy of the model fit and predictions. Results: Twenty-four subjects contributed to 900 midazolam concentrations. The final parameter estimates (% relative standard error, RSE) were as follows; clearance (CL), 31.8 L/h (6.0%); inter-compartmental clearance (Q) 2, 36.4 L/h (9.7%); Q3, 7.37 L/h (12.0%), volume of distribution (V) 1, 70.7 L (3.6%), V2, 32.9 L (8.8%); and V3, 44.4 L (6.7%). The midazolam CL decreased and increased to 32.5 and 199.9% in the inhibition and induction phases, respectively, compared to that in control phase. Conclusion: A PK model for midazolam co-treatment with ketoconazole and rifampicin was developed using data of healthy volunteers, and the subject's CYP3A status influenced the midazolam PK parameters. Therefore, a population PK model with enzyme-mediated drug interactions may be useful for quantitatively predicting PK alterations.

• Molecular & Cellular Toxicology
• /
• v.5 no.4
• /
• pp.346-353
• /
• 2009

Drug metabolism is a critical determinant of the therapeutic and adverse effects of many psychotropic drugs. The metabolism depends on the pharmacokinetics of a drug, which includes its absorption, distribution, and elimination. Psychotropic drugs are metabolized mainly by cytochrome P450 (CYP) enzymes; about 20 of these enzymes exist and they are often responsible for the rate-limiting step of drug metabolism. CYP2D6 is the best-characterized P450 enzyme that exhibits polymorphism in humans. This study determined the relationship between the CYP2D6*10 (P34S) polymorphism and the response to mirtazapine in 153 Koreans with major depressive disorder (MDD). The genotype frequencies were compared using logistic regression analysis, and between-genotype differences in the decrease in the 21-item Hamilton Depression (HAMD21) score over the 12-week treatment period were analyzed using a linear regression analysis. The proportion of remitters was lower in patients with MDD possessing the S allele than in P allele carriers after 2 weeks of mirtazapine treatment. Similarly, the reductions in the HAMD21 and Clinical Global Impression (CGI) scores in S allele carriers were smaller than those in patients with the P allele after 2 weeks of mirtazapine treatment. In the analysis of depression symptoms, the sleep and delusion scores had smaller reductions in S allele carriers. Based on the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS), the psychic adverse effects of mirtazapine were associated with CYP2D6 P34S, while weight gain was not. These results suggest that CYP2D6 P34S affects the outcome of mirtazapine treatment in patients with MDD, and that this polymorphism may be a good genetic marker for predicting the clinical outcome of mirtazapine treatment.

• Journal of Marine Life Science
• /
• v.8 no.2
• /
• pp.104-114
• /
• 2023

As plastic usage increases globally, the amount of plastic waste entering the marine environment is steadily rising. Microplastics, in particular, can be ingested by marine organisms and accumulated in their digestive tracts, causing harmful effects on their growth and reproduction. Cytochrome P450 (CYP) enzymes are known to metabolize various environmental pollutants as detoxification enzymes, but their role in crustaceans is not well understood. In this study, sequences of nine CYP genes (CYP370A4, CYP370C5 from clan 2; CYP350A1, CYP350C5, CYP361A1 from clan 3; CYP4AN-like, CYP4AP2, CYP4AP3, CYP4C33-like1 from clan 4) were analyzed using conserved domains in the brackish water flea Diaphanosoma celebensis. Additionally, after exposure to three different sizes of polystyrene beads (0.05-, 0.5-, 6-㎛ PS beads; 0.1, 1, and 10 mg/L) for 48 hours, the expression of these nine CYP genes were investigated using real-time reverse transcription polymerase chain reaction (RT-PCR). The results showed that all CYP genes possessed conserved motifs, indicating that D. celebensis CYP has evolutionarily conserved functions. Among these CYP genes, the expression of CYP370C5, CYP360A1, and CYP4C122 showed a significant increase after exposure to 0.05-㎛ PS beads, suggesting their involvement in PS metabolism. This research will contribute to understanding the molecular mode of actions of microplastics on marine invertebrates.

• BMB Reports
• /
• v.40 no.3
• /
• pp.448-452
• /
• 2007

We examined the contribution of CYP2C9 and CYP2C19 genotypes and drug interactions to the phenytoin metabolism among 97 Korean epileptic patients to determine if pharmacogenetic testing could be utilized in routine clinical practice. The CYP2C9 polymorphism is a wellknown major genetic factor responsible for phenytoin metabolism. The CYP219 polymorphism, with a high incidence of variant alleles, has a minor influence on phenytoin treated Koran patients. Using a multiple regression model for evaluation of the CYP2C9 and CYP2C19 genotypes, together with other non-genetic variables, we explained 39.6% of the variance in serum phenytoin levels. Incorporation of genotyping for CYP2C9 and CYP2C19 into a clinical practice may be of some help in the determination of phenytoin dosage. However, because concurrent drug treatment is common in patients taking phenytoin and many environmental factors are likely to play a role in drug metabolism, these factors may overwhelm the relevance of CYP polymorphisms in the clinical setting. Further investigations with an approach to dose assessment that includes comprehensive interpretation of both pharmacogenetic and pharmacokinetic data along with understanding of the mechanism of drug interactions in dosage adjustment is warranted.

• Asian Pacific Journal of Cancer Prevention
• /
• v.13 no.9
• /
• pp.4549-4553
• /
• 2012

This study was designed to investigate the frequency of CYP2D6 polymorphisms and evaluate the association between genetic polymorphisms of CYP2D6 and tamoxifen therapeutic outcome in Thai breast cancer patients. We recruited 48 breast cancer patients who received adjuvant tamoxifen for evaluating CYP2D6 genetic polymorphisms using microarray-based technology. Associations between genotypes-phenotypes and disease free survival were analyzed. Median follow up time was 5.6 years. The mean age of the subjects was 50 years. The 3 common allelic frequencies were 43.8% ($^*10$), 36.5 ($^*1$) and 10.4% ($^*2$) which are related to extensive metabolizer (EM) and intermediate metabolizer (IM) with 70.8% and 29.2 %, respectively. No association between CYP2D6 genotypes and DFS was demonstrated. Nevertheless, exploratory analysis showed statistically significant shorter DFS in the IM group of post-menopause patients (HR, 6.85; 95%CI, 1.48-31.69; P=0.005). Furthermore, we observed statistically significant shorter DFS of homozygous $CYP2D6^*10$ when compared with heterozygous CYP2D6*10 and other genotypes (P=0.005). $CYP2D6^*10$ was the most common genotype in our subjects. Post-menopause patients with homozygous $CYP2D6^*10$ and IM have shorter DFS. To confirm this relationship, larger samples and comprehensively designed trials in Thailand are required.

• BMB Reports
• /
• v.41 no.6
• /
• pp.472-478
• /
• 2008

Three Arabidopsis cDNAs, MAM1, CYP79F1, and CYP83A1, required for aliphatic glucosinolate biosynthesis were introduced into Chinese cabbage by Agrobacterium tumefaciens-mediated transformation. The transgenic lines overexpressing MAM1 or CYP83A1 showed wild-type phenotypes. However, all the lines overexpressing CYP79F1 displayed phenotypes different from wild type with respect to the stem thickness as well as leaf width and shape. Glucosinolate contents of the transgenic plants were compared with those of wild type. In the MAM1 line M1-1, accumulation of aliphatic glucosinolates gluconapin and glucobrassicanapin significantly increased. In the CYP83A1 line A1-1, all the aliphatic glucosinolate levels were increased, and the levels of gluconapin and glucobrassicanapin were elevated by 4.5 and 2 fold, respectively. The three CYP79F1 transgenic lines exhibited dissimilar glucosinolate profiles. The F1-1 line accumulated higher levels of gluconapoleiferin, glucobrassicin, and 4-methoxy glucobrassicin. However, F1-2 and F1-3 lines demonstrated a decrease in the levels of gluconapin and glucobrassicanapin and an increased level of 4-hydroxy glucobrassicin.