• Toxicological Research
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• 제9권1호
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• pp.35-44
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• 1993

Role of rat cytochrome P-450 2E1(P-450 2E 1) in the metabolism of chlorzoxazone was examined by using several approaches' (1) selective inhibiton of catalytic activity in rat liver microsomes by diethyldithiocarbamate, (2) correlation of dimethylnitrosomine N-demethylation with chlorzoxazone 6-hydroxylation, and (3) immunoinhibition of catalytic activity with rabbit anti-rat P-450. The results indicated that P-450 2E1 is responsible for the metabolism of chlorzoxazone.

• The Korean Journal of Physiology and Pharmacology
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• 제1권5호
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• pp.597-602
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• 1997

Cytochrome P450 2E1 (CYP2E1) is involved in the toxicity and carcinogenicity of a number of solvents and xenobiotics. Like the various types of oxidation pharmacogenetics, the activity of the enzyme shows a discernible interindividual and interethnic variation. However, no pharmacogenetic information on CYP2E1 polymorphism has been available from a Korean population. The aim of this study was to explore the pharmacogenetics of CYP2E1 polymorphism in a native Koreans after an oral 400 mg dose of chlorzoxazone administered to 128 subjects. Urine samples were collected during the subsequent 8-hour period and urinary concentrations of chlorzoxazone and 6-hydroxychlorzoxazone were determined by a high performance liquid chromatography with an ultraviolet detector. The limit of detection in the samples was found to be $0.5\;{\mu}g/ml$. The mean value of the 6-hydroxychlorzoxazone excreted in 8 hr urine expressed as the percentage was 48.2 13.8%. The frequency distribution of percentage of the administered dose excreted as the 6-hydroxy metabolite was unimodally distributed in the subjects studied. However, the values showed wide (7-fold) interindividual difference, ranged from 11.6% to 79.8% of the dose of chlorzoxazone. Thus, it was considered that the pharmacogenetic characteristics of CYP2E1 in a Korean population did not represent multimodal distribution in the 6-hydroxychlorzoxazone excreted in 8-hr urine expressed as the percentage. And the activity of the CYP2E1 in a Korean population seemed to be less compared with that of the Caucasian subjects.

• Toxicological Research
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• 제24권3호
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• pp.195-199
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• 2008

It has been reported that hepatic microsomal cytochrome P450(CYP) 2E1 is responsible for the metabolism of chlorzoxazone(CZX) to 6-hydroxychlorzoxazone. The present study was undertaken to assess the possible interaction of rutaecarpine, an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa, with CZX. Male Spraque-Dawley rats were administered with 80 mg/kg/day of oral rutaecarpine for three consecutive days. Twenty four hr after the pre-treatment with rutaecarpine, the rats were treated with 20 mg/kg of intravenous CZX. Rat hepatic microsomes isolated from rutaecarpine-treated rats showed greater(50% increase) activity of p-nitrophenol hydroxylase(a marker of CYP2E1) when compared with the control rats. Compared with control rats, the AUC of CZX was significantly smaller(84% decrease) possibly due to significantly faster CL(646% increase) in rats pretreated with rutaecarpine. This could be, at least partially, due to induction of CYP2E1 by rutaecarpine.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.1
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• pp.308.2-309
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• 2003

In rats with water deprivation for 72 h (rats with dehydration), hepatic cytochrome P450 2E1 (CYP2E1) was 3-fold induced with an increase in mRNA, and glucose supplementation instead of food during 72-h water deprivation inhibited the CYP2E1 induction. Chlorzoxazone (CZX) is metabolized to 6-hydroxychlorzoxazone (OH-CZX) mainly by CYP2E1 in rats. (omitted)

• 대한약학회:학술대회논문집
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• 대한약학회 2000년도 NEW STRATEGY FOR DRUG DEVELOPMENT IN POST-GENOMIC ERA(대한약학회)
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• pp.273.1-273.1
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• 2000

• Toxicological Research
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• 제22권1호
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• pp.1-8
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• 2006

The primary metabolism of pyribenzoxim was studied in rat liver microsomes in order to identify the cytochrome P450 (CYP) isoform(s) and esterases involved in the metabolism of pyribenzoxim. Chemical inhibition using CYP isoform-selective inhibitors such as ${\alpha}$-naphthoflavone, tolbutamide, quinine, chlorzoxazone, troleandomycin, and undecynoic acid indicated that CYP1A and CYP2D are responsible for the oxidative metabolism of pyribenzoxim. And inhibitory studies using eserine, bis-nitrophenol phosphate, dibucaine, and mercuric chloride indicated pyribenzoxim hydrolysis involved in microsomal carboxylesterases containing an SH group (cysteine) at the active center.

• Toxicological Research
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• 제19권3호
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• pp.235-240
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• 2003

The modification of CYP2E1 activity is of considerable interest because of its role in the metabolic activation of a variety of toxic chemicals. In the present studies, the time-course of changes in human CYP2E1 activities was determined after treatment with ethanol, glycerol, 4-methylpyrazole or isoniazid using intact HepG2 cells transfected by human CYP2E1. Hydroxylation of chlorzoxazone was chosen for the measurement of CYP2E1 activity. CYP2E1 protein levels were increased upon cultivation of cells in the presence of ethanol, glycerol, 4-methylpyrazole or isoniazid for 24 hr. After 24 hr cultivation, ethanol or glycerol increased CYP2E1 activities, whereas 4-methylpyrazole or isoniazid inhibited. This different effect of the chemical inducers on CYP2E1 activi-ties persisted to subsequent 24 hr. Competitive inhibition study suggested that 4-methylpyrazole or isoniazid has stronger binding affinity to CYP2E1 than ethanol or glycerol. These results demonstrate that different binding affinity of the chemical inducers to the active site of CYP2E1 plays important role in determining real CYP2E1 activity in intact cells after treatment with the chemical inducers. Present study would be helpful in precise understanding of human CYP2E1-mediated toxicity.

• 한국환경보건학회지
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• 제29권3호
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• pp.9-15
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• 2003

The modification of CYP2El activity is a matter of considerable interest because of its role in the metabolic activation of a variety of environmental toxicants. In the present study, the time-course of changes in human CYP2El activities was determined following treatment with solvents (acetone, dimethylsulphoxide or pyridine) using intact HepG2 cells transfected by human CYP2El. Hydroxylation of chlorzoxazone was used for the measurement of CYP2El activity. CYP2E1 protein level was increased upon cultivation of cells in the presence of the solvents for 24 hr. Determination of CYP2El activities after 24 ht cultivation with the solvents demonstrated that acetone or dimethylsulphoxide increased, whereas pyridine inhibited the activities. This differential effect of the solvents on CYP2El activities persisted to subsequent 24 ht. Competitive inhibition study suggested that pyridine has stronger binding affinity to CYP2E1 than acetone or dimethylsulphoxide. These results demonstrate that different binding affinity of the solvents to CYP2El plays important role in determining real CYP2El activity in intact cells after exposure to the solvents. Present study would be helpful in precise understanding of human CYP2El-mediated toxicity.

• Mass Spectrometry Letters
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• 제3권4호
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• pp.104-107
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• 2012

Mollugin isolated from Rubia cordifolia is known to have anti-inflammatory, anti-cancer, and anti-viral activities. In the present study, a cocktail probe assay and LC-MS/MS were used to investigate the modulating effect of mollugin on cytochrome P450 (CYP) enzymes in male ICR mice. After mollugin was orally administrated to mice at the 20, 40, or 80 mg/kg for 3 days, the activities of CYP in hepatic S-9 fractions were investigated. Unlike the selective inhibitory effect of mollugin on CYP1A2-catalyzed phenacetin O-deethylation in vitro, mollugin only significantly inhibited the activity of CYP2E1-catalyzed chlorzoxazone 6-hydroxylase in vivo. The activities of other CYPs were only slightly altered by mollugin. The results of this study suggest that mollugin might cause herb-drug interactions via the selective inhibition of CYP2E1 in vivo.

• 한국임상약학회지
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• 제24권1호
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• pp.45-52
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• 2014

Objective: To evaluate the clinical manifestations and causative drugs of the outpatient adverse drug reactions (ADRs) reported by community pharmacy. Methods: From April 2013 to September 2013, all outpatient ADRs reported by community pharmacy to Regional Pharmacovigilance Center of Korean Pharmaceutical Association were included. The causality of ADRs was assessed by the criteria of WHO-Uppsala Monitoring Centre. The clinical features and the offending drugs were analyzed using the WHO-Adverse Reaction Terminology and the classification of American Hospital Formulary Service Drug Information, respectively. Results: 2,826 (97.0%) of the total 2,912 ADRs had causal relationship. The 1,923 patients with mean age of 55.1 years and female fraction of 66.5% were included in the ADRs. Gastrointestinal (33.6%), nervous system (14.9%), and skin (13.5%) symptoms were common in ADRs. Analgesic drugs (19.7%), gastrointestinal drugs (17.7%), and central nervous system drugs (11.0%) were prevalent offending drugs. The leading causative generic drug was the complex of acetaminophen and tramadol. Among 203 ADRs by the nonprescription drugs, the most common clinical features were skin (37.4%) and gastrointestinal (23.6%) symptoms and the most prevalent offending drugs were analgesic drugs (40.0%) and mucocutaneous system drugs (16.3%). The combination of acetaminophen and chlorzoxazone was the leading causative generic in nonprescription drugs. Conclusion: In this study, gastrointestinal symptom was the most common manifestation and analgesic drug was the most common causative drug in outpatient ADRs reported by community pharmacy.