• Asian Pacific Journal of Cancer Prevention
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• 제15권1호
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• pp.495-499
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• 2014

Estrogens are considered the major breast cancer risk factor, and the carcinogenic potential of estrogens might be attributed to DNA modification caused by derivatives formed during metabolism. $17{\beta}$-estradiol ($E_2$), the main steroidal estrogen present in women, is metabolized via two major pathways: formation of 2-hydroxyestradiol (2-OH $E_2$) and 4-hydroxyestradiol ($4-OH\;E_2$) through the action of cytochrome P450 (CYP) 1A1 and 1B1, respectively. Previous reports suggested that $2-OH\;E_2$ has putative protective effects, while $4-OH\;E_2$ is genotoxic and has potent carcinogenic activity. Thus, the ratio of $2-OH\;E_2/4-OH\;E_2$ is a critical determinant of the toxicity of $E_2$ in mammary cells. In the present study, we investigated the effects of berberine on the expression profile of the estrogen metabolizing enzymes CYP1A1 and CYP1B1 in breast cancer MCF-7 cells. Berberine treatment produced significant induction of both forms at the level of mRNA expression, but with increased doses produced 16~ to 52~fold greater induction of CYP1A1 mRNA over CYP1B1 mRNA. Furthermore, berberine dramatically increased CYP1A1 protein levels but did not influence CYP1B1 protein levels in MCF-7 cells. In conclusion, we present the first report to show that berberine may provide protection against breast cancer by altering the ratio of CYP1A1/CYP1B1, could redirect $E_2$ metabolism in a more protective pathway in breast cancer MCF-7 cells.

• 환경생물
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• 제24권2호
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• pp.195-200
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• 2006

The response of hepatic mixed function oxygenase (MFO) system was investigated in olive flounder exposed to formalin. Hepatic microsome of olive flounder incubated in vitro with formalin demonstrated the induction of cytochrome P450 (CYP), ethoxyresorufin deethylase (EROD), cytochrome P450 reductase (P450R) and cytochrome b5 reductase (b5R) activity. In addition, olive flounder was exposed to 100, 300 and 500 ppm of formalin for 1 h and then transferred to a flow-through type of 1000 L aquarium. Hepatic MFO enzyme activity was determined for 72 h. As the result, hepatic CYP, P450R and EROD activities increased following exposure of formalin, but b5R and GST showed no significant change. These results imply that CYP and P450R can be considered as main hepatic enzymes involving in detoxification of formalin.

• Asian Pacific Journal of Cancer Prevention
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• 제17권7호
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• pp.3335-3340
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• 2016

Background: Oral submucous fibrosis (OSF) is a precancerous condition with a 4 to13% malignant transformation rate. Related to the habit of areca nut chewing it is mainly prevalent in South-east Asian countries where the habit of betel quid chewing is frequently practised. On chewing, alkaloids and polyphenols are released which undergo nitrosation and give rise to N-nitrosamines which are cytotoxic agents. CYP450 is a microsomal enzyme group which metabolizes various endogenous and exogenous chemicals including those released by areca nut chewing. CYP1A1 plays a central role in metabolic activation of these xenobiotics, whereas CYP2E1 metabolizes nitrosamines and tannins. Polymorphisms in genes that code for these enzymes may alter their expression or function and may therefore affect an individuals susceptibility regarding OSF and oral cancer. The present study was therefore undertaken to investigate the association of polymorphisms in CYP1A1 m2 and CYP2E1 (RsaI/PstI) sites with risk of OSF among areca nut chewers in the Northern India population. A total of 95 histopathologically confirmed cases of OSF with history of areca nut chewing not less than 1 year and 80, age and sex matched controls without any clinical signs and symptoms of OSF with areca nut chewing habit not less than 1 year were enrolled. DNA was extracted from peripheral blood samples and polymorphisms were analyzed by PCR-RFLP method. Gene polymorphism of CYP1A1 at NcoI site was observed to be significantly higher (p = 0.016) in cases of OSF when compared to controls. Association of CYP1A1 gene polymorphism at NcoI site and the risk of OSF (Odd's Ratio = 2.275) was also observed to be significant. However, no such association was observed for the CYP2E1 gene polymorphism (Odd's Ratio = 0.815). Our results suggest that the CYP1A1 gene polymorphism at the NcoI site confers an increased risk for OSF.

• Biomolecules & Therapeutics
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• 제22권2호
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• pp.149-154
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• 2014

Effects of diallyl sulfide (DAS) on thioacetamide-induced hepatotoxicity and immunotoxicity were investigated. When male Sprague-Dawley rats were treated orally with 100, 200 and 400 mg/kg of DAS in corn oil for three consecutive days, the activity of cytochrome P450 (CYP) 2E1-selective p-nitrophenol hydroxylase was dose-dependently suppressed. In addition, the activities of CYP 2B-selective benzyloxyresorufin O-debenzylase and pentoxyresorufin O-depentylase were significantly induced by the treatment with DAS. Western immunoblotting analyses also indicated the suppression of CYP 2E1 protein and/or the induction of CYP 2B protein by DAS. To investigate a possible role of metabolic activation by CYP enzymes in thioacetamide-induced hepatotoxicity, rats were pre-treated with 400 mg/kg of DAS for 3 days, followed by a single intraperitoneal treatment with 100 and 200 mg/kg of thioacetamide in saline for 24 hr. The activities of serum alanine aminotransferase and aspartate aminotransferase significantly elevated by thioacetamide were protected in DAS-pretreated animals. Likewise, the suppressed antibody response to sheep erythrocytes by thioacetamide was protected by DAS pretreatment in female BALB/c mice. Taken together, our present results indicated that thioacetamide might be activated to its toxic metabolite(s) by CYP 2E1, not by CYP 2B, in rats and mice.

• Biomolecules & Therapeutics
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• 제19권2호
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• pp.237-242
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• 2011

This study was designed to investigate the effects of glipizide on the pharmacokinetics of carvedilol after oral or intravenous administration of carvedilol in rats. Clinically carvedilol and glipizide can be prescribed for treatment of cardiovascular diseases as the complications of diabetes, and then, Carvedilol and glipizide are all substrates of CYP2C9 enzymes. Carvedilol was administered orally or intravenously without or with oral administration of glipizide to rats. The effects of glipizide on cytochrome P450(CYP) 2C9 activity and P-gp activity were also evaluated. Glipizide inhibited CYP2C9 activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of 18 ${\mu}M$. Compared with the control group, the area under the plasma concentration-time curve (AUC) was significantly increased by 33.0%, and the peak concentration ($C_{max}$) was significantly increased by 50.0% in the presence of glipizide after oral administration of carvedilol. Consequently, the relative bioavailability (R.B.) of carvedilol was increased by 1.13- to 1.33-fold and the absolute bioavailability (A.B.) of carvedilol in the presence of glipizide was increased by 36.8%. After intravenous administration, compared to the control, glipizide could not significantly change the pharmacokinetic parameters of carvedilol. Therefore, the enhanced oral bioavailability of carvedilol may mainly result from inhibition of CYP2C9-mediated metabolism rather than both P-gp-mediated effl ux in the intestinal or in the liver and renal elimination of carvedilol by glipizide.

• 한국동물생명공학회지
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• 제35권4호
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• pp.329-337
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• 2020

Cytochrome P450 1A2 (CYP1A2) is a member of the cytochrome P450 superfamily enzymes in mammals and plays a major role in metabolizing endogenous hormones in the liver. In recent days, CYP1A2 expression has been found in not only the liver but also other tissues including the pancreas and lung. However, little information is available regarding the expression of CYP1A2 in the ovary, in spite of the facts that the ovarian follicle growth and atresia are tightly associated with controls of endocrine hormonal networks. Therefore, the expression of CYP1A2 in the ovaries of prepubertal and pubertal rats was investigated to assess its expression pattern and puberty-related alteration. It was demonstrated that the expression level of CYP1A2 was significantly (p < 0.01) higher in the pubertal ovaries than prepubertal counterparts. At the ovarian follicle level in both groups, whereas CYP1A2 expression was less detectable in the primordial, primary and secondary follicles, the strongly positive expression of CYP1A2 was localized in the granulosa cell layers in the antral and pre-ovulatory follicles. However, the ratio of CYP1A2-positive ovarian follicle was significantly (p < 0.01) higher in the ovary of pubertal group (73.1 ± 3.1%) than prepubertal one (41.0 ± 10.5%). During the Immunofluorescence, expression of CYP1A2 was mainly localized in Fas-positive follicles, indicating the atretic follicles. In conclusion, these results suggested that CYP1A2 expression was mainly localized at the atretic follicular cells and affected by the onset of puberty. Further study is still necessary but we hypothesize that CYP1A2 expresses in the atretic follicles to metabolize residue of the reproductive hormones. These findings may have important implications for the fields of reproductive biology of animals.

• Archives of Pharmacal Research
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• 제27권2호
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• pp.239-245
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• 2004

KR-31543, (2S,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2 -methyl-2H-tetrazol-5-ylmethyl) amino]-3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-2H-1-benzopyran, is a new neuroprotective agent for preventing ischemia-reperfusion damage. This study was performed to identify the metabolic pathway of KR-31543 in human liver microsomes and to characterize cytochrome P450 (CYP) enzymes that are involved in the metabolism of KR-31543. Human liver microsomal incubation of KR-31543 in the presence of NADPH resulted in the formation of two metabolites, M1 and M2. M1 was identified as N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine on the basis of LC/MS/MS analysis with a synthesized authentic standard, and M2 was suggested to be hydroxy-KR-31543. Correlation analysis between the known CYP enzyme activities and the rates of the formation of M 1 and M2 in the 12 human liver microsomes have showed significant correlations with testosterone 6$\beta$-hydroxylase activity (a marker of CYP3A4). Ketoconazole, a selective inhibitor of CYP3A4, and anti-CYP3A4 monoclonal antibodies potently inhibited both N-hydrolysis and hydroxylation of KR-31543 in human liver microsomes. These results provide evidence that CYP3A4 is the major isozyme responsible for the metabolism of KR-31543 to M1 and M2.

• Toxicological Research
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• 제17권
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• pp.145-155
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• 2001

Cytochrome P4502C19 (CYP2C19) is one of human polymorphic xenobiotic-metabolizing enzymes. The enzyme has been reported to catalyze more than 70 substrates, involving more than 100 reactions. These include several classes of therapeutic agents (e.g. anti-microbial. cardiovascular, psycho-active, etc.), sex hormones and insecticides. Associations of the CYP2C19 genotype/phenotype with individual differences in drug efficacy (e.g. diazepam, omeprazole, proguanil) and toxicity (e.g. mephenytoin, barbiturates) have been documented by many investigators. At least 11 allelic variants of CYP2C19 gene were reported to date. Most of the mutant alleles found in the poor metabolizer (PM) led to the production of truncated and/or inactive proteins. Except for the exon 6, single-nucleotide mutations were reported in all nine exons of the gene. Genetic polymorphism of CYP2C19 shows marked interethnic variation with the population frequencies of PM phenotype ranging from 1∼2% up to more than 50%. The prevalence of CYP2C19 PM tends to be higher in Asian and certain Pacific Islanders than other race or ethnic specificity. Genotyping results of CYP2C19 also revealed that there are different proportions of individual mutant alleles among ethnic populations. This may, in part, explains the interethnic difference in the metabolism of certain drugs (i.e. diazepam), though they were from the same CYP2C19 phenotype. Recently, our research group has studied the genotype and phenotype of CYP2C19 and found that the PM frequency (7∼8%) in Thais is lower than other Asian populations. Molecular and clinical impacts of this finding warrant to further investigation.

• 대한한의학회지
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• 제28권1호통권69호
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• pp.51-62
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• 2007

Objectives . The types of Sasang constitutional medicine (SCM) have definite effect on response to herbal drugs. The majority of human P45O dependent xenobiotic metabolism is carried out by polymorphic enzymes which can cause abolished, altered or enhanced metabolism. Therefore, we evaluated the relation of major CYP2C19, 2D6 polymorphism with Sasang types. Methods : 214 healthy subjects were recruited with informed consent; 172 among them had Sasang diagnosis by QSCC2. CYP2D6, 2C19 polymorphism were determined by PCR-RFLP method. Results : None of the Sasang types showed significant difference in CYP2D6, 2C19 polymorphism. However, the Tae-um type showed relatively low frequency of CYP2D6 $^{*}$10/$^{*}$10 polymorphisms with low activity (p=0.110). In the So-yang type, specific $^{*}$3/$^{*}$3 genotype which is a poor metabolizer of CYP2C19$^{*}$3 was detected (p=0.078).Conclusion . These results suggest that the Tae-um type which is said to have high liver function in SCM has the tendency of high drug-metabolizing enzyme activity. With further study, the CYP polymorphism could serve as a scientific tool for SCM diagnosis.

• BMB Reports
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• 제35권6호
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• pp.615-622
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• 2002

The purpose of this study was to determine the effects of dietary garlic powder on diethylnitrosamine (DEN)-induced hepatocarcinogenesis and cytochrome P450 (CYP) enzymes in weaning male Sprague-Dawley rats by using the medium-term bioassay system of Ito et al. The rats were fed diets that contained 0, 0.5, 2.0 or 5.0% garlic powder for 8 weeks, beginning the diets with the intraperitoneal (i.p.) injection of DEN. The areas of placental glutathione S-transferase (GST-P) positive foci, an effective marker for DEN-initiated lesions, were significantly decreased in the rats that were fed garlic-powder diets; the numbers were significantly decreased only in the 2.0 and 5.0% garlic-powder diets. The p-nitrophenol hydroxylase (PNPH) activities and protein levels of CYP 2E1 in the hepatic microsomes of the rats that were fed the 2.0 and 5.0% garlic powder diet were much lower than those of the basal-diet groups. Pentoxyresorufin O-dealkylase (PROD) activity and CYP 2B1 protein level were not influenced by the garlic-powder diets and carcinogen treatment. Therefore, the suppression of CYP 2E1 by garlic in the diet might influence the formation of preneoplastic foci during hepatocarcinogenesis in rats that are initiated with DEN.