• Parasites, Hosts and Diseases
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• 제51권2호
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• pp.165-175
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• 2013

The fear that schistosomes will become resistant to praziquantel (PZQ) motivates the search for alternatives to treat schistosomiasis. The antimalarials quinine (QN) and halofantrine (HF) possess moderate antischistosomal properties. The major metabolic pathway of QN and HF is through cytochrome P450 (CYP) 3A4. Accordingly, this study investigates the effects of CYP3A4 inhibitor, ketoconazole (KTZ), on the antischistosomal potential of these quinolines against Schistosoma mansoni infection by evaluating parasitological, histopathological, and biochemical parameters. Mice were classified into 7 groups: uninfected untreated (I), infected untreated (II), infected treated orally with PZQ (1,000 mg/kg) (III), QN (400 mg/kg) (IV), KTZ (10 mg/kg)+QN as group IV (V), HF (400 mg/kg) (VI), and KTZ (as group V)+HF (as group VI) (VII). KTZ plus QN or HF produced more inhibition (P<0.05) in hepatic CYP450 (85.7% and 83.8%) and CYT b5 (75.5% and 73.5%) activities, respectively, than in groups treated with QN or HF alone. This was accompanied with more reduction in female (89.0% and 79.3%), total worms (81.4% and 70.3%), and eggs burden (hepatic; 83.8%, 66.0% and intestinal; 68%, 64.5%), respectively, and encountering the granulomatous reaction to parasite eggs trapped in the liver. QN and HF significantly (P<0.05) elevated malondialdehyde levels when used alone or with KTZ. Meanwhile, KTZ plus QN or HF restored serum levels of ALT, albumin, and reduced hepatic glutathione (KTZ+HF) to their control values. KTZ enhanced the therapeutic antischistosomal potential of QN and HF over each drug alone. Moreover, the effect of KTZ+QN was more evident than KTZ+HF.

• Archives of Pharmacal Research
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• 제28권10호
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• pp.1196-1202
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• 2005

Omeprazole (OMP) is a proton pump inhibitor used as an oral treatment for acid-related gastrointestinal disorders. In the liver, it is primarily metabolized by cytochrome P-450 (CYP450) isoenzymes such as CYP2C19 and CYP3A4. 5-Hyroxyomeprazole (5-OHOMP) and omeprazole sulfone (OMP-SFN) are the two major metabolites of OMP in human. Cimetidine (CMT) inhibits the breakdown of drugs metabolized by CYP450 and reduces, the clearance of coad-ministered drug resulted from both the CMT binding to CYP450 and the decreased hepatic blood flow due to CMT. Phenobarbital (PB) induces drug metabolism in laboratory animals and human. PB induction mainly involves mammalian CYP forms in gene families 2B and 3A. PB has been widely used as a prototype inducer for biochemical investigations of drug metabolism and the enzymes catalyzing this metabolism, as well as for genetic, pharmacological, and toxicological investigations. In order to investigate the influence of CMT and PB on the metabolite kinetics of OMP, we intravenously administered OMP (30 mg/kg) to rats intraperitoneally pretreated with normal saline (5 mL/kg), CMT (100 mg/kg) or PB (75 mg/kg) once a day for four days, and compared the pharmacokinetic parameters of OMP. The systemic clearance ($CL_{t}$) of OMP was significantly (p<0.05) decreased in CMT-pretreated rats and significantly (p<0.05) increased in PB-pretreated rats. These results indicate that CMT inhibits the OMP metabolism due to both decreased hepatic blood flow and inhibited enzyme activity of CYP2C19 and 3A4 and that PB increases the OMP metabolism due to stimulation of the liver blood flow and/or bile flow, due not to induction of the enzyme activity of CYP3A4.

• 대한한의학회지
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• 제38권2호
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• pp.15-30
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• 2017

Objectives: Hwangryunhaedok-tang (HHT; Huanglianjiedu-tang, Orengedoku-to), a traditional herbal formula, is used for treating inflammation, hypertension, gastritis, liver dysfunction, cerebrovascular diseases, dermatitis and dementia. The objective of this study was to assess the sub-acute toxicity of HHT in Sprague-Dawley (SD) rats, and its effect on the activities of human microsomal cytochrome P450s (CYP450s) and UDP-glucuronosyltransferases (UGTs). Methods: Male and female SD rats were orally administered HHT once daily at doses of 0, 500, 1000 and 2000 mg/kg for 4 weeks. We analyzed mortality, clinical observations, body weight, food consumption, organ weights, urinalysis, hematology, serum biochemistry, and histopathology. The activities of major human CYP450s (CYP1A2, CYP3A4, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP2E1) and UGTs (UGT1A1, UGT1A4, and UGT2B7) were assessed using in vitro fluorescence- and luminescence-based enzyme assays, respectively. Results: No toxicologically significant changes related to the repeated administration of HHT were observed in both male and female SD rats. The no observed adverse effect level (NOAEL) value was more than 2000 mg/kg/day for both sexes. HHT inhibited the activities of human microsomal CYP1A2, CYP2C19, CYP2D6, and CYP2E1, whereas it weakly inhibited the activities of CYP2B6, CYP2C9, CYP3A4, and UGT1A1. In addition, HHT negligibly inhibited the activities of human microsomal UGT1A4 and UGT2B7 with $IC_{50}$ values in excess of $1000{\mu}g/mL$. Conclusions: Our findings indicate that HHT may be safe for repeated administration up to 4 weeks. In addition, these findings provide information on the safety and effectiveness of HHT when co-administered with conventional drugs.

• 동의생리병리학회지
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• 제21권6호
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• pp.1415-1423
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• 2007

Carbon tetrachloride ($CCl_4$)-induced liver injury depends on a toxic agent that has to be metabolized by the liver NAPDH-cytochrome P450 enzyme system to a highly reactive intermediate. Alternations in the activity of cytochrome P450 enzymes affect the susceptibility to hepatic injury from $CCl_4$. In this study, we evaluated the potential protective activity of the traditional Korean medicinal herb, Corni fructus (CF), against an experimental model of hepatotoxicity induced by $CCl_4$. The CF exhibited a hepatoprotective activity against $CCl_4-induced$ liver damage in Sprague-Dawley (SD) rats, as measured by GOT, GPT, ALP and histological observation. The CF also showed significant decrease of malodialdehyde (MDA) and increase of glutathion (GSH), catalase activity in rat liver homogenate. In addition, the expression of CYP2E1, as measured by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis, was significantly decreased in the liver of CF treated SD rats. But $CCl_4$ and CF has no significant effect on 1A1 and 3A1 isoform of cytochrome P450. Based on these findings, it is suggested that hepatoprotective effects of CF possibly related to antioxidative effects and regulation of CYP2E1 expression.

• 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.

• Mass Spectrometry Letters
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• 제12권4호
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• pp.172-178
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• 2021

HYIpro-3-1 is an adjuvant for preventing or treating inflammatory growth diseases. In this study, we identified the metabolic pathway of HYIpro-3-1 in human liver microsomes (HLMs) by quadrupole-orbitrap high-resolution mass spectrometry (HR-MS) and characterized the major human cytochrome P450 (CYP). Ten metabolites were identified, including one O-demethylation (M1), two O-demethylation and monohydroxylation (M2 and M3), and seven monohydroxylation metabolites (M4-M10). Based on the HR-MS² spectra, the metabolites are divided into two groups of monohydroxylated metabolites according to the hydroxylation position. We verified that HYIpro-3-1 is metabolized by CYP in HLMs, CYP2B6 is mainly involved in O-demethylation, and various CYPs are involved in the monohydroxylation of HYIpro-3-1.

• 생약학회지
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• 제50권3호
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• pp.159-164
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• 2019

Zanthoxylum Peel is widely used as a common spice for a variety of foods. In the orient, it has also been used as traditional agents for treating diseases such as indigestion. Recently, Zanthoxylum Peel has been reported to have anti-cancer activity, anti-microbial activity, and anti-inflammatory activity. Chemical components are known sanshool compounds and xanthoxylin. In this study, we were carried out to investigate the constituents of inhibiting a drug metabolizing enzyme CYP3A4 from Zanthoxylum Peel. CYP3A4 is known as an enzyme involved in drug metabolism as monooxygenase containing the heme. As a result of experiment, we found that bergapten ($IC_{50}=18.21{\mu}M$) and quercetin ($IC_{50}=17.27{\mu}M$) isolated from EtOAc extract of Zanthoxylum Peel showed remarkable CYP3A4-inhibiting activities. Structures of the isolated active compounds were established by chemical and spectroscopic means.

• 한국산업보건학회지
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• 제21권1호
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• pp.49-54
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• 2011

In order to develop the methods for exposure assessment and find susceptibility markers for the workers who are exposed to low doses of toluene, xylene and other chemical in petroleum industries, we investigated the application of P-450 expression in human lymphocytes utilizing mouse monoclonal anti-rat CYP2B1/2, the levels of toluene and xylene in air and their metabolite levels in urine with the levels of expressed CYP2B1/2 proteins. The general characteristics such as age, smoking and drinking habit were no significant difference between the control and exposed workers, but the working durations and working hours were significantly different. Workers in exposed group were exposed to the mean of 2.1 ppm (range, 0.00-4.54) of toluene and 0.3 ppm (rang, 0.00-1.23) of xylene. The mean concentration of urinary hippuric acid was low and less than 1/5 of the biological exposure index recommended by the Ministry of Employment and Labor Korea. Methyl hippuric acid in urine was not detected in control and exposed workers. Also, there were no significant differences in the levels of the urinary metabolites between the control and exposed group. When chemiluminescence dot blottings were carried out utilizing mouse monoclonal antibody against CYP2B1/2, the strong density dots corresponding to a mouse monoclonal antibody was observed in the human lymphocytes from the exposed workers. These results suggested that the chemiluminescence dot blot assay for CYP of lymphocytes should be valuable for identifying CYP expression as biomarkers in the workers exposed to toluene and xylene.

• 생명과학회지
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• 제17권3호통권83호
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• pp.334-339
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• 2007

본 연구는 우황청심원을 비롯한 상용되는 20종의 한약제제를 대상으로 9종의 시토크롬 동종효소에 대한 대사능의 저해정도를 고속 스크리닝 기법을 이용하여 탐색함으로써, 한약제제와 약물의 병용으로 인한 약물 상호작용 가능성을 평가하고자 하였다. 인체 간 마이크로좀 시료에 9종의 주요 시토크롬 약물대사효소의 지표약물과NADPH-generating system및 한약제제(500 ${\mu}g/ml$)를 첨가한 후 $37^{\circ}C$에서 15분간 반응시켜 생성된 각각의 대사물을 LC/MS/MS를 이용하여 정량하여 시토크롬 동종효소 활성의 변화를 평가하였다. 그 결과 우황청심원 현탁액 및 황련해독탕 물 추출물이 각각 CYP2B6 및 CYP2D6 효소 활성을 선택적으로 강력하게 저해하였다. 이러한 결과는 약국에서 쉽게 구입할 수 있는 한약제제들 중 일부는 인체 간 시토크롬 활성 저해능을 가지고 있고, 이들 효소에 의해 대사되는 약물과의 병용 복용시 약물상호작용 발생 가능성이 있음을 의미한다. 향후 한약제제에서 저해능을 나타내는 주된 성분을 규명하여 이 성분의 저해능과 저해 기전을 살피는 노력이 필요할 것이다.

• Advances in Traditional Medicine
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• 제7권4호
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• pp.357-362
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• 2007

Cytochrome P450 2C19 (CYP2C19) is a clinically important enzyme involved in the metabolism of therapeutic drugs, including (S)-mephenytoin, omeprazole, proguanil, and diazepam. Individuals are characterized as either extensive metabolizers (EM) or poor metabolizers (PM) on the basis of CYP2C19 enzyme activity. The PM phenotype occurs in 2-5% of Caucasians, but in 18-23% of Asians. To clarify the association between CYP2C19 polymorphisms and gastric cancer in Koreans, we investigated CYP2C19 genotypes ($CYP2C19^*1,\;{^*2},\;and\;^*3$) in 109 patients with gastric cancer and 211 controls. Normal ($CYP2C19^*1$) and defective alleles were detected with polymerase chain reaction/restriction enzyme analysis. CYP2C19 has three hereditary genotypes: homozygous EM, with high enzymatic activity; heterozygous EM, with moderate enzymatic activity; and PM, with no enzyme activity. We found that CYP2C19 heterozygous EM is more closely associated with gastric cancer than is homozygous EM. Because the CYP2C19 genotype varies in Koreans, a genotyping test is desirable to prevent gastropathy recurrence in patients before their doses of omeprazole are reduced during maintenance therapy.