• Korean Journal of Clinical Pharmacy
• /
• v.33 no.4
• /
• pp.242-253
• /
• 2023

Background: Arrhythmia due to QT prolongation is one of the most serious adverse events with drug interactions in the elderly. This study aimed to examine the incidence of arrhythmia in Korean elderly patients who administered both cytochrome P450 3A4 (CYP3A4) substrates and inhibitors. Methods: Patients using CYP3A4 substrate and inhibitor were selected from the 2017 elderly patient dataset (the Korean Health Insurance Review and Assessment Service - Aged Population Sample). Selection criteria were patients with a medication possession ratio over 80%, medication duration of at least 7 days, and a follow-up period of 3 months or more. The patient's basic information is age, gender, health insurance type, and comorbidities. The top 50 drug pairs and comorbidity with high-incidence arrhythmia were presented. Results: In patients with drug combinations for over 7 days, there were 981 incidences of arrhythmia, and 351 incidences in those with combinations for over 30 days. The comorbidities of congestive heart failure and myocardial infarction had a significant association with incidence of arrhythmia. Among patients with 7 days or longer, the drug pairs [substrates-inhibitors] with significant adjusted odds ratio (aOR) were [propranolol-cimetidine] (aOR, 2.25; 95% confidence interval [CI], 1.66-3.04). Among patients with 30 days or longer, the drug pairs with significant aOR were [tramadol-amiodarone] (aOR, 2.87; 95% CI, 1.97-4.19). Conclusions: In elderly patients, the incidence of arrhythmia was high with drug interactions of CYP3A4 substrates and inhibitors. The comorbidity of congestive heart failure was the risk factor.

• Journal of Korean Medical Science
• /
• v.33 no.53
• /
• pp.298.1-298.10
• /
• 2018

Background: The renal function of individuals is one of the reasons for the variations in therapeutic response to various drugs. Patients with renal impairment are often exposed to drug toxicity, even with drugs that are usually eliminated by hepatic metabolism. Previous study has reported an increased plasma concentration of indoxyl sulfate and decreased plasma concentration of $4{\beta}$-hydroxy (OH)-cholesterol in stable kidney transplant recipients, implicating indoxyl sulfate as a cytochrome P450 (CYP) inhibiting factor. In this study, we aimed to evaluate the impact of renal impairment severity-dependent accumulation of indoxyl sulfate on hepatic CYP3A activity using metabolic markers. Methods: Sixty-six subjects were enrolled in this study; based on estimated glomerular filtration rate (eGFR), they were classified as having mild, moderate, or severe renal impairment. The plasma concentration of indoxyl sulfate was quantified using liquid chromatography-mass spectrometry (LC-MS). Urinary and plasma markers ($6{\beta}$-OH-cortisol/cortisol, $6{\beta}$-OH-cortisone/cortisone, $4{\beta}$-OH-cholesterol) for hepatic CYP3A activity were quantified using gas chromatography-mass spectrometry (GC-MS). The total plasma concentration of cholesterol was measured using the enzymatic colorimetric assay to calculate the $4{\beta}$-OH-cholesterol/cholesterol ratio. The correlation between variables was assessed using Pearson's correlation test. Results: There was a significant negative correlation between MDRD eGFR and indoxyl sulfate levels. The levels of urinary $6{\beta}$-OH-cortisol/cortisol and $6{\beta}$-OH-cortisone/cortisone as well as plasma $4{\beta}$-OH-cholesterol and $4{\beta}$-OH-cholesterol/cholesterol were not correlated with MDRD eGFR and the plasma concentration of indoxyl sulfate. Conclusion: Hepatic CYP3A activity may not be affected by renal impairment-induced accumulation of plasma indoxyl sulfate.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.23
• /
• pp.10187-10192
• /
• 2015

Cytochrome P450 (CYP) enzymes are a large family of constitutive and inducible mono-oxygenase enzymes that play a central role in the oxidative metabolism of both xenobiotic and endogenous compounds. Several CYPs are involved in metabolism of oxysterols, which are cholesterol oxidation products whose expression may be dysregulated in inflammation-related diseases including cancer. This study focused on CYP39A1, which can metabolize 24-hydroxycholesterol (24-OH) that plays important roles in the inflammatory response and oxidative stress. We aimed to investigate the expression status of CYP39A1 and its transcription factor (RUNX2) in relation to clinical significance in cholangiocarcinoma (CCAs) and to determine whether 24-OH could induce oxidative stress in CCA cell lines. Immunohistochemistry showed that 70% and 30% of CCA patients had low and high expression of CYP39A1, respectively. Low expression of CYP39A1 demonstrated a significant correlation with metastasis. Our results also revealed that the expression of RUNX2 had a positive correlation with CYP39A1. Low expression of both CYP39A1 (70%) and RUNX2 (37%) was significantly related with poor prognosis of CCA patients. Interestingly, oxidized alpha-1 antitrypsin (ox-A1AT), an oxidative stress marker, was significantly increased in CCA tissues in which CYP39A1 and RUNX2 were down regulated. Additionally, immunocytochemistry showed that 24-OH could induce ox-A1AT in CCA cell lines. In conclusion, our study revealed putative roles of the CYP39A1 enzyme in prognostic determination of CCAs.

• Preventive Nutrition and Food Science
• /
• v.1 no.2
• /
• 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 Microbiology and Biotechnology
• /
• v.14 no.1
• /
• pp.158-161
• /
• 2004

Scenedesmus spp. were cultured for 51 days in newly developed medium, KEP I (Kim and Ecopeace: initials of corresponding author and environmental company) made with Bacterio-Mineral-Water (3%, v/v) that had been bio-reacted with swine urine medium to 10% (v/v) Bold's Basal medium, and investigated for cancer chemopreventive potential by measuring the induction of quinone reductase (QR), glutathione S-transferase (GST), and reduced glutathione (GSH), and inhibition of cytochrome P450 (CYP) 1A1 activity. The activitives of QR and GST of Scenedesmus spp. cultured in KEP I medium were increased by 3.0-fold and 1.5-fold, respectively. However, Scenedesmus spp. cultured in control medium (CT) increased the activitives of QR and GST by 1.8-fold and 1.3-fold, respectively. Scenedesmus spp. in KEP I medium strongly inhibited CYP 1Al activity. These results show that Scenedesmus spp. in KEP I medium has cancer chemopreventive potential and may be a candidate for further development as a chemopreventive agent.

• Korean Journal of Fisheries and Aquatic Sciences
• /
• v.36 no.6
• /
• pp.573-577
• /
• 2003

Effects of 4-nonylphenol (4-NP) on mixed function oxygenase (MFO) in the kidneies of rockfish (Sebastes schlegeli) were investigated. The cytochrome P45O (CYP) contents and NADPH cytochrome P450 reductase, NADH cytochrome b5 reductase and 7-ethoxyredorufin-O-deethylase (EROD) activities of microsome, glutathione S-transferase (GST) activity of cytosol in rockfish exposed to 4-NP for 7 days using an intraperitoneal injection (25 mg/kg) were quantitatively determined. The GST activity of rockfish exposed to 4-NP were higher, up to 5.2 times higher, than those in the control fish. The activities of NADPH-and NADH-dependent reductases were inhibited. On the other hand, CYP contents and EROD activity of the 4-NP exposed fish demonstrated neither an increasing or decreasing trend.

• Korean Journal of Head & Neck Oncology
• /
• v.19 no.2
• /
• pp.148-157
• /
• 2003

Background and Objectives: Individual genetic susceptibilities to chemical carcinogens have been recognized as a major important host factors in human cancers. The cytochrome P450 family (CYPs) and glutathione S-transferase(GST) have been reported to be associated with risks to the smoking-related human cancers. Inactivation of tumor suppressor genes like p53 playa key role in tumor progression. The purpose of this study is to demonstrate an association between p53 overexpression and the prevalence of the genetic polymorphisms of CYP1A1 and GSTs in Korean head and neck squamous cell carcinoma (HNSCC). Materials and Methods: The polymorphisms of CYPIA1 and GSTs were analyzed by PCR and PCR-RFLP in 98 Korean head and neck squamous cell carcinoma patients. The expression of p53 was analyzed by immunohistochemistry with anti-p53 Ab (DO7). Results: Overexpression of p53 detected in 45.9% of HNSCC. The odds ratio for p53 overexpression in GSTM1(-), GSTT1(-), GSTP1(val/val) and CYP1A1(val/val) were 1.53, 1.83, 1.17 and 1.47, respectively. Among the combined genotypes, the odds ratio of the CYP1A1 val/val, GSTM1 (-), CYP1A1 val/val, GSTT1(-), and CYP1A1 val/val, GSTT1(-) were 2.0, 2.34 and 4.68, respectively. Conclusion: Based on our results, it might be suggested that p53 overexpression is slightly increased in GSTM1(-), GSTT1(-), GSTP1 val/val, CYP1A1 val/val genotypes. The further study is needed to evaluate the relationship and mechanism between the p53 overexpression and the specific CYP1A1 and GSTs genotypes.

• Journal of Preventive Medicine and Public Health
• /
• v.55 no.3
• /
• pp.280-288
• /
• 2022

Objectives: One of the most widely used pesticides today is chlorpyrifos (CPF). Cytochrome P450 (CYP)2B6, the most prominent catalyst in CPF bioactivation, is highly polymorphic. The objective of our study was to evaluate the role of CYP2B6^*6, which contains both 516G>T and 785A>G polymorphisms, in CPF toxicity, as represented by the concentration of 3,5,6-trichloro-2-pyridinol (TCPy), among vegetable farmers in Central Java, Indonesia, where CPF has been commonly used. Methods: A cross-sectional study was conducted among 132 vegetable farmers. Individual socio-demographic and occupational characteristics, as determinants of TCPy levels, were obtained using a structured interviewer-administered questionnaire and subsequently used to estimate the cumulative exposure level (CEL). TCPy levels were detected with liquid chromatography-mass spectrometry. CYP2B6^*6 gene polymorphisms were analyzed using a TaqMan^® SNP Genotyping Assay and Sanger sequencing. Linear regression analysis was performed to analyze the association between TCPy, as a biomarker of CPF exposure, and its determinants. Results: The prevalence of CYP2B6^*6 polymorphisms was 31% for ^*1/^*1, 51% for ^*1/^*6, and 18% for ^*6/^*6. TCPy concentrations were higher among participants with CYP2B6^*1/^*1 than among those with ^*1/^*6 or ^*6/^*6 genotypes. CYP2B6^*6 gene polymorphisms, smoking, CEL, body mass index, and spraying time were retained in the final linear regression model as determinants of TCPy. Conclusions: The results suggest that CYP2B6^*6 gene polymorphisms may play an important role in influencing susceptibility to CPF exposure. CYP2B6^*6 gene polymorphisms together with CEL, smoking habits, body mass index, and spraying time were the determinants of urinary TCPy concentrations, as a biomarker of CPF toxicity.

• Journal of Aquaculture
• /
• v.16 no.2
• /
• pp.99-103
• /
• 2003

Olive flounder (Paralichthys olivaceus) was exposed to water-borne phenanthrene for 4 weeks. After the exposure for 2-weeks, hepatic cytochrome P450 contents were significantly elevated. Induction of hepatic ethoxy resorufin-O-deethylase (PROD) activity was significantly increased in flounders treated with 1.0 and 2.0 $\mu$M phenanthrene, compared to untreated group and 0.5 $\mu$M treated group. However, there were no significant changes in pentoxyresorufin-O-deethylase (PROD) activity in hepatic microsome of all the phenanthrene-treated groups, compared to the untreated group. Phenanthrene has the potential to induce cytochrome P450 and EROD enzyme of the olive flounder.

• Korean Journal of Biological Psychiatry
• /
• v.7 no.1
• /
• pp.21-33
• /
• 2000

As the clinical practice of using more than one drug at a time increase, the clinician is faced with ever-increasing number of potential drug interactions. Although many interactions have little clinical significances, some may interfere with treatment or even be life-threatening. This review provides a better understanding of drug-drug interactions often encountered in pharmacotherapy of depression. Drug interactions can be grouped into two principal subdivisions : pharmacokinetic and pharmacodynamic. These subgroups serve to focus attention on possible sites of interaction as a drug moves from the site of administration and absorption to its site of action. Pharmacokinetic processes are those that include transport to and from the receptor site and consist of absorption, distribution on body tissue, plasma protein binding, metabolism, and excretion. Pharmacodynamic interactions occur at biologically active sites. In this review, emphasis is placed on antidepressant medications, how they are metabolized by the P450 system, and how they alter the metabolism of other drugs. When prescribing antidepressant medications, the clinician must consider the drug-drug interactions that are potentially problematic.