• The Korean Journal of Physiology and Pharmacology
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• v.1 no.5
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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.

• Archives of Pharmacal Research
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• v.26 no.12
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• pp.1079-1086
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• 2003

The aim of this study was to investigate the effect of trauma on cytochrome P450 (CYP) gene expression and to determine the role of Kupffer cells in trauma-induced alteration of CYP isozymes. Rats underwent closed femur fracture (FFx) with associated soft-tissue injury under anesthesia. To deplete Kupffer cells in vivo, gadolinium chloride ($GdCl_3$) was intravenously injected at 7.5 mg/kg body wt., 1 and 2 days prior to FFx surgery. At 72 h of FFx, liver tissues were isolated to determine the mRNA and protein expression of CYP isozymes and NADPH-P450 reductase by reverse transcription-polymerase chain reaction and Western immunoblotting, respectively. In addition, the mRNA levels of tumor necrosis factor alpha (TNF-$\alpha$), inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1) were evaluated. FFx increased the mRNA level of CYP1A1; an increase that was not prevented by $GdCl_3$. There were no significant differences in the mRNA expression of CYP1A2, 2B1 and 2E1 among any of the experimental groups. The protein levels of CYP2B1 and 2E1 were significantly decreased by FFx; a decrease that was not prevented by $GdCl_3$ treatment. The gene expression of NADPH-P450 reductase was unchanged by FFx. FFx significantly increased the expression of TNF-$\alpha$ mRNA; an increase that was attenuated by $GdCl_3$. The mRNA expression of HO-1 was increased by FFx, but not by $GdCl_3$ . Our findings suggest that FFx differentially regulates the expression of CYP isozyme through Kupffer cell-independent mechanisms.

• Archives of Pharmacal Research
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• v.27 no.2
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• pp.232-238
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• 2004

Trolox is a hydrophilic analogue of vitamin E. The aim of this study was to investigate its effects on hepatic injury, especially alteration in cytochrome P450 (CYP)-dependent drug metabolism during polymicrobial sepsis. Rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). The rats were treated intravenously with Trolox (2.5 mg/kg) or vehicle, immediately after CLP. Serum aminotransferases and lipid peroxidation levels were markedly increased 24 h after CLP. This increase was attenuated by Trolox. Total CYP content and NADPH-P450 reductase activity decreased significantly 24 h after CLP. This decrease in CYP content was attenuated by Trolox. At 24 h after CLP, there was a significant decrease in the activity of these CYP isozymes: CYP1A1, 1A2, 2B1, and 2E1. However, Trolox differentially inhibited the decrease in CYP isozyme activity. Trolox had little effect on the decrease in CYP1A1 activity but Trolox significantly attenuated decreases in CYP1A2 and 2E1 activities. In fact, Trolox restored CYP2B1 activity to the level of activity found in control rats. Our findings suggest that Trolox reduces hepatocellular damage as indicated by abnormalities in hepatic drug-metabolizing function during sepsis. Our data also indicates that this protection is, in part, caused by decreased lipid peroxidation.

• Mass Spectrometry Letters
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• v.3 no.4
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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.

• Korean Journal of Acupuncture
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• v.24 no.1
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• pp.161-170
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• 2007

Objectives : In this study, we determinated protective effects of Vitis labrusca Root herbal-acupuncture solution (VLHA) against atherosclerosis and cardiovascular disease induced by oxidative damage and cytochrome P450 (CYP) induction. Methods : Antioxidant capacity of VLHA were evaluated by the ${\beta}-carotene/linoleic$ acid emulsion system and FeCl2-ascorbic acid stimulted lipid peroxidation in rat liver homogenate, respectively. Scavenging effects of VLHA on ONOO- and NO were measured by DHR 123, DAF-2 assay. Furthermore, we measured inhibitory activity of VLHA on CYP 2E1 in rat liver microsome using by Aniline assay. Results : VLHA exhibited potent inhibition rate(74%) on FeCl2-ascorbic acid induced lipid peroxidation, and revealed a strong scavenging effects on ONOO- and NO. In addition, VLHA showed inhibitory effect on CYP 2E1. Conclusions : The present study concludes that our results suggest that VLHA could be used as a good source in the prevention of atherosclerosis and alcoholic liver injury.

• The Journal of Korean Medicine
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• v.35 no.2
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• pp.47-59
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• 2014

Objectives: Most drug interactions are attributed to the inhibition or induction of the activity of cytochrome P450s (CYP450). Although the regulation of CYP450s by drugs has been widely reported, there have been few studies on influence of traditional herbal formulas on the drug-metabolizing enzymes. Because herbal formulas have been used traditionally to treat various diseases and because herb-drug interactions are crucial factors determining therapeutic efficacies, a systematic evaluation of the effects of herbal formulas is important. Methods: The effects of Galgeun-tang (GGT, gegen tang), Gumiganghwal-tang (GMGHT, jiuweiqianghuo tang), Insampaedok-san (ISPDS, renshenbaidu powder), Samsoeum (SSE, shensu drink), Socheongryong-tang (SCRT, xiaoqinglong-tang) and Sosiho-tang (SSHT, xiaochaihu tang) that are traditional herbal formulas used to treat common cold, on drug-metabolizing enzymes were evaluated through an in vitro CYP3A4, CYP2D6, CYP2C19 and CYP2E1 inhibition assay to assess its interaction potential with synthetic drugs. The inhibitory effects of herbal formulas were characterized with $IC_{50}$ values. Results: These six herbal formulas inhibited the activities of CYP3A4, 2C19, 2D6 and 2E1, in a concentration-dependent manner. Among the six herbal formulas, GGT critically inhibited CYP2C19, CYP2D6 and CYP2E1. GMGHT also inhibited CYP2D6 and CYP2E1 to a greater extent than the other CYP450 isozymes. Additionally, SSE and SSHT may change the effects of medicines that depend primarily on the CYP2C19 and CYP2E1 pathways. On the other hand, ISPDS and SCRT were not inhibited CYP3A4, CYP2C19, CYP2D6 and CYP2E1-mediated metabolism. Conclusions: These findings provide useful information regarding the safety and effectiveness of herbal formulas.

• Journal of the Korean Society of Food Science and Nutrition
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• v.26 no.4
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• pp.682-688
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• 1997

This study was performed to investigate whether ascorbic acid can modulate the induction of CYP2E1 and prevent the lipid peroxidation which may cause diabetic chronic complication. Diabetes was induced by intraperitoneal injection of streptozotocin to 5-week-old male Sprague-Dawley rats(150~170g). Normal and diabetic group was randomly divided into three groups each; Control(CON, no supplementation), SUP1 (50mg/d ascorbate supplementation) and SUP2(250mg/d ascorbate supplementation). Ascobic acid was prepared daily by dissolving in drinking water and supplied for 4 weeks. There was no difference in hepatic microsomal and mitochondrial P450 contents between normal and diabetes. Hepatic microsomal N-nitrosodimethylamine(NDMA) demethylase activity, which repre-sents contents of CYP2E1, was elevated in diabetes, but not significantly. The NDMA demethylase activity of diabetic SUP2 group was significantly lower activity than that of the diabetic CON group. However, no difference in hepatic mitochondrial NDMA demethylase activity was observed between the diabetes and the normal group. The result suggests that the induction of CYP2E1 in diabetes can be alleviated by ascorbic acid supplementation at the dose of 50mg1d. In addition, ascorbic acid supplementation showed dose-dependent reduction of hepatic microsomal TBARS contents in diabetic rats.

• Biomolecules & Therapeutics
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• v.14 no.4
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• pp.189-193
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• 2006

This study was designed to assess the distribution of cytochrome P450 2E1 (CYP2E1) polymorphism among Korean patients on warfarin therapy. CYP2E1 polymorphism was analyzed at 5' flanking region of CYP2E1 gene using restriction fragment length polymorphism method. Patient characteristics including the measured internal normalized ratio (INR) were also evaluated. Based on the warfarin dose and the bleeding cases, the patients were grouped as the regular dose control, the regular dose bleeding, the low dose control, and the low dose bleeding. Total 96 patients were evaluated for both Pst I and Rsa I loci of the CYP2E1 gene and the results showed that both loci were tightly linked. Thirty-three patients(34.4%) were heterozygotes and 4 patients(4.2%) were homozygote. There was no significant difference in patient characteristics in the dose and bleeding case groups. CYP2E1 polymorphism showed a little difference among the groups but was not statistically significant, however, lower INR value was observed in homozygote genotype groups. It was also revealed that genotype allele frequencies of CYP2E1 in Korean was close to other Asian groups but was significantly different from other Caucasian and African-American populations.

• Archives of Pharmacal Research
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• v.26 no.1
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• pp.47-52
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• 2003

The aim of this study was to investigate the effects of trauma on alterations in cytochrome P450 (CYP 450)-dependent drug metabolizing function and to determine the role of Kupffer cells in hepatocellular dysfunction. Rats underwent closed femur fracture (FFx) with associated soft-tissue injury under anesthesia, while control animals received only anesthesia. To deplete Kupffer cells in vivo, gadolinium chloride (GdCl$_3$) was injected intravenously via the tail vein at 7.5 mg/kg body wt., 1 and 2 days prior to FFx surgery. At 72 h after FFx, serum alanine aminotransferase (ALT) activity was increased, and this increase was attenuated by GdCl$_3$ pretreatment. Serum aspartate aminotransferase (AST) and lipid peroxidation levels were not changed by FFx. Hepatic microsomal CYP 450 content and aniline p-hydroxylase (CYP 2E1) activity were significantly decreased; decreases that were not prevented by GdC1$_3$. The level of CYP 2B1 activity was decreased by Kupffer cell inactivation, but not by FFx. There were no significant differences in the activities of CYP 1A1, CYP 1A2 and NADPH-CYP 450 reductase among any of the experimental groups. Our findings suggest that FFx trauma causes mild alterations of hepatic CYP 450-dependent drug metabolism, and that Kupffer cells are not essential for the initiation of such injury.

• Clinical and Experimental Reproductive Medicine
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• v.28 no.2
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• pp.131-140
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• 2001

Objective: To know the effects of xenoestrogen on spermatogenesis, we investigated the expression of cytochrome P450s enzymes (CYPscc, $CYP_{17{\alpha}}$, CYP19) and $3{\beta}$-HSD genes involved in steroidogenesis. Methods: Mouse testicular cells were prepared from 15-day-old ICR mice which had only pre-meiotic germ cells by enzyme digestion using collagenase and trypsin. Testicular cells were cultured in DMEM supplemented with FSH (0.1 IU/ml) and 10% FBS or medium with estrogen ($E_2$), bisphenol-A (BPA), octylphenol (OP; $10^{-9},\;10^{-7},\;10^{-6},\;10^{-5},\;10^{-4}M$, respectively) and aroclor 1254 (A1254) known as PCBs for 48 hours. The gene expression of cytochrome P450 enzymes were examined by semi-quantitive RT-PCR. The production of estrogen and testosterone was examined by RIA. Results: As results, expression of CYPscc mRNA was not significantly decreased, but $3{\beta}$-HSD and $CYP_{17{\alpha}}$. mRNA were significantly dose-dependent decreased. And production of testosterone and estrogen were not different except BPA and OP group ($10^{-5}M$). Conclusion: BPA, OP and A1254 might inhibit steroidogenesis by decreasing CYPscc, $3{\beta}$-HSD and $CYP_{17{\alpha}}$. mRNA expression in the mouse testis. These results suggest that BPA, OP and PCBs like as an endocrine disruptors inhibit the productions of steroidogenic enzymes and decrease the production of T and E by negative feedback mechanism. Therefore, these might disrupt steroidogenesis in Leydig cells of testis and would disturb testicular function and subsequently impair spermatogenesis.