Flavonoids are present in fruits, vegetables and beverages derived from plants, and in many dietary supplements or herbal remedies. A number of naturally occurring flavonoids have been shown to modulate the CYP450 system, including the induction or inhibition of these enzymes. This review focuses on the flavonoid effects on cytochrome P450 (CYP) enzyme CYP1, 2E1, 3A4 and 19. Flavonoids alter CYPs by various mechanisms, including the stimulation of gene expression via specific receptors and/or CYP protein, or mRNA stabilization and so on. But in vivo and in vitro, the effects of flavonoids are not always coincident as a result of concentrations of flavonoids, genetic and environmental factors. As well, flavonoids may interact with drugs through the induction or inhibition of their metabolism. Much attention should be paid to the metabolism interaction of the flavonoids when coadministered with other drugs.
Animals ; Aromatase ; genetics ; metabolism ; Cytochrome P-450 CYP1A1 ; antagonists & inhibitors ; genetics ; metabolism ; Cytochrome P-450 CYP2E1 ; genetics ; metabolism ; Cytochrome P-450 CYP2E1 Inhibitors ; Cytochrome P-450 CYP3A ; genetics ; metabolism ; Cytochrome P-450 CYP3A Inhibitors ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System ; genetics ; metabolism ; Enzyme Activation ; drug effects ; Flavonoids ; pharmacology ; Humans ; RNA, Messenger ; genetics ; metabolism

<p>OBJECTIVETo establish a convenient and efficient model for investigating the expression of CYP3A4 and drug metabolism in vitro.p><p>METHODS1alpha,25-dihydroxyvitamin D3 was utilized as an inducer to enhance CYP3A4 expression in HepG2 cells. 0.1, 0.25, 0.35 micromol/L 1alpha,25-dihydroxyvitamin D3 were added to the cell culture media, and cells were harvested after 24, 48, 72 and 96 hours. Cell proliferation was determined with MTT assay. CYP3A4 mRNA level was analyzed with RT-PCR and expressions of CYP3A4 protein were measured by Western blot.p><p>RESULTS1alpha,25-dihydroxyvitamin D3 in 3 concentrations, namely 0.10, 0.25 and 0.35 micromol/L, did not show obvious toxicity to HepG2 cells. At 24 h of the cultivation, the expression of CYP3A4 mRNA was not increased significantly, but CYP3A4 mRNA expression significantly increased by 120%, 134%, 200% at 48 h, by 174%, 254%, 420% at 72 h, and by 258%, 450%, 370% at 96 h, respectively under the three concentrations. Similar results were observed in the induction of CYP3A4 protein expression. At 48, 72 and 96 hours after treatment with 0.25 micromol/L and 0.35 micromol/L 1alpha,25-dihydroxyvitamin D3, CYP3A4 protein increased in various folds in the controls (1.2 and 2.2 after 48 h, 3.4 and 6.5 after 72 h, 6.1 and 7.2 after 96 h), while 0.10 micromol/L 1alpha,25-dihydroxyvitamin D3 only induced protein expression at 72 h and 96 h (1.8 and 4.1 folds, respectively).p><p>CONCLUSION1alpha,25-dihydroxyvitamin D3 could induce the expression of CYP3A4 mRNA as well as CYP3A4 protein in HepG2, which provides a convenient and efficient in vitro system for investigation of CYP3A4 and drug interaction.p>
Calcitriol ; pharmacology ; Cytochrome P-450 CYP3A ; drug effects ; genetics ; metabolism ; Hep G2 Cells ; Humans ; Transcription, Genetic

OBJECTIVE: To assess the association of cytochrome P450 (CYP450) gene polymorphisms with the occurrence of ischemic stroke (IS). METHODS: From January 2020 to August 2022, 390 IS patients treated at the Zhengzhou Seventh People's Hospital were enrolled as the study group, and 410 healthy individuals undergoing physical examination during the same period were enrolled as the control group. Clinical data of all subjects were collected, which included age, sex, body mass index (BMI), smoking history and results of laboratory tests. Chi-square test and independent sample t test were used for comparing the clinical data. Multivariate logistic regression analysis was used to analyze the non-hereditary independent risk factors for IS. Fasting blood samples of the subjects were collected, and the genotypes of rs4244285, rs4986893, rs12248560 of the CYP2C19 gene and rs776746 of the CYP3A5 gene were determined by Sanger sequencing. The frequency of each genotype was calculated by using SNPStats online software. The association between the genotype and IS under the dominant, recessive and additive models was analyzed. RESULTS: The levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C), apolipoprotein B (Apo-B) and homocysteine (Hcy) of the case group were significantly higher than those of the control group, whilst the levels of high density lipoprotein (HDL-C) and Apo-A1 (APO-A1) were significantly lower (P < 0.05). Multivariate Logistic regression analysis showed that TC (95%CI = 1.13-1.92, P = 0.02), LD-C (95%CI = 1.03-2.25, P = 0.03), Apo-A1 (95%CI = 1.05-2.08, P = 0.04), Apo-B (95%CI = 1.7-4.22, P < 0.01) and Hcy (95%CI = 1.12-1.83, P = 0.04) were non-genetic independent risk factors for the occurrence of IS. Analysis of the association between the genetic polymorphisms and the risk of IS showed that the AA genotype at rs4244285 of the CYP2C19 gene, the AG genotype and A allele at rs4986893 of the CYP2C19 gene, and the GG genotype and G allele at rs776746 of the CYP3A5 gene were significantly associated with IS. Under the recessive/additive model, dominant model and dominant/additive model, polymorphisms of the rs4244285, rs4986893 and rs776746 loci were also significantly associated with the IS. CONCLUSION TC, LDL-C, Apo-A1, Apo-B and Hcy can all affect the occurrence of IS, and CYP2C19 and CYP3A5 gene polymorphisms are closely associated with the IS. Above finding has confirmed that the CYP450 gene polymorphisms can increase the risk of IS, which may provide a reference for the clinical diagnosis.
Humans ; Cytochrome P-450 CYP3A/genetics* ; Cytochrome P-450 CYP2C19/genetics* ; Ischemic Stroke ; Cholesterol, LDL/genetics* ; Polymorphism, Single Nucleotide ; Genotype ; Apolipoproteins B/genetics* ; Gene Frequency

OBJECTIVE: To assess the association of CYP2C19 and CYP3A5 gene polymorphisms with the risk of myocardial infarction. METHODS: Five hundred patients with myocardial infarction and 500 healthy controls were randomly selected. Fluorescent PCR and Sanger sequencing were used to detect the CYP2C19 and CYP3A5 gene polymorphisms. Logistic regression was used to analyze the correlation between the polymorphisms and myocardial infarction. Quanto software was used to evaluate the statistical power. RESULTS: The two groups had significant difference in the frequency of AG, GG genotypes and A allele of the CYP2C19 gene rs4986893 locus and the AA, AG, GG genotypes and G allele of the CYP3A5 gene rs776746 locus ( P<0.05), but not in the frequency of genotypes and alleles of CYP2C19 gene rs4244285 and rs12248560 loci, and the AA genotype of the rs4986893 locus. After correction for age, gender, and body mass index, Logistic regression indicated that the AG genotype and A allele of the CYP2C19 gene rs4986893 locus, and the GG genotype and G allele of CYP3A5 gene rs776746 locus are associated with susceptibility of myocardial infarction, while rs4986893 GG genotype and AA and AG genotypes of rs776746 may confer a protective effect. Based on the sample size and allele frequency, analysis with Quanto software suggested that the result of this study has a statistical power of 99%. CONCLUSION CYP2C19 and CYP3A5 gene polymorphisms may increase the risk for myocardial infarction.
Cytochrome P-450 CYP2C19/genetics* ; Cytochrome P-450 CYP3A/genetics* ; Gene Frequency ; Genotype ; Humans ; Myocardial Infarction/genetics* ; Polymorphism, Genetic ; Polymorphism, Single Nucleotide

The present work was to study induction of cytochrome P450 (CYP)3A and CYP2H1 gene by reverse transcriptase polymerase chain reaction (RT-PCR) and quantitative RTPCR in Bantam, Bantamized White Leghorn and White Leghorn chicks. Out of 18 chicks total 3 from each group (Bantam, Bantamized White Leghorn and White Leghorn) were treated intraperitoneal with phenobarbital at the dose rate of 12 mg/100 g (body weight) while the control group was treated with the saline. Total RNA was extracted from the liver samples using Tri Reagent based method. First strand cDNA was synthesized using one step RT-PCR kit. The PCR was performed and the product was subjected to agarose gel electrophoresis. Quantitative RT-PCR was conducted to quantify gene expression level of CYP3A and CYP2H1 genes. Relative expression ratio of CYP3A and CYP2H1 genes was calculated using relative expression software tool (REST). It was found that CYP3A is up regulated by factor of 1.34, 14.51 and 1.00 in Bantam, Bantamized White Leghorn and White Leghorn chicks, respectively. In Bantam and Bantamized White Leghorn chicks CYP2H1 gene was up regulated by factor 1.50 and 80.87, respectively but down regulated by a factor of 1.97 in White Leghorn chicks. The PCR efficiency ranged from 1.30 to 1.70, 0.86 to 1.70 and 0.91 to 1.58 for CYP3A, CYP2H1 and beta-actin, respectively in Bantam, Bantamized White Leghorn and White Leghorn chicks.
Animals ; Chickens/*metabolism ; Cytochrome P-450 CYP3A/*biosynthesis/genetics ; Cytochrome P-450 Enzyme System/*biosynthesis/genetics ; Gene Expression Regulation/drug effects ; Phenobarbital/*pharmacology ; Reverse Transcriptase Polymerase Chain Reaction

<p>OBJECTIVETo investigate if CYP3A5 is involved in drug resistances mechanisms of acute leukemia.p><p>METHODSBy using RT-PCR, immunohistochemistry and MTT assay, CYP3A5 mRNA and protein were detected in leukemia cell lines and acute leukemia patients, meanwhile transcriptional regulation of CYP3A5 induced by daunorubicin was observed. A pcDNA3-CYP3A5 reconstituted plasmid and its stably transfected cell line HL-60/CYP3A5 were both established.p><p>RESULTSCYP3A5 mRNA was detected in K562 and U937 cells, whose IC(50) values of daunorubicin were 2.1-fold higher than those of NB4 and HL-60 cells. Bone marrow CYP3A5 positive blast cell percentage at the time of diagnosis in primary drug resistance group (17.2%) was significantly higher than that of continuous complete remission (CCR) group (0.4%) and secondary drug resistance group (5.4%). In their first complete remission of the early relapsed group, the positive rate had been 23.9% as compared with that of CCR group (1.3%). Daunorubicin increased CYP3A5 mRNA level in K562/A02 and activated its transcription in HL-60/ADR. HL-60/CYP3A5 cell was significantly resistant to daunorubicin and vincristine than HL-60 cells did (3.0 and 4.0 times, respectively).p><p>CONCLUSIONCYP3A5 expressed in leukemia cells may cause in situ metabolization of many kinds of anticancer drugs, thus led to drug resistance.p>
Cytochrome P-450 CYP3A ; Cytochrome P-450 Enzyme System ; genetics ; physiology ; Daunorubicin ; pharmacology ; Drug Resistance, Neoplasm ; Humans ; Leukemia ; drug therapy ; enzymology ; RNA, Messenger ; analysis ; Tumor Cells, Cultured

<p>OBJECTIVETo establish a RP-HPLC method for the determination of amlodipine after metabolism by cytochrome P450 cDNA-expressed cells.p><p>METHODSThe determination was performed on a C(18) reversed phase column with a mobile phase composed of acetonitrile phosphates buffer (45:55, v/v, pH 4.5) with UV detection (lambda250nm). Propranolol was used as the internal standard.p><p>RESULTThe standard curve was linear over the concentration range of 0.2 - 30.0 microg/ml (r=0.9993), and the limits of determination was 20 ng/ml (S/N >or=3), the limits of quantity was 0.2 microg/ml (recovery 104.0%, RSD 11.4%, n=5). The recovery for this assay was (98.2+/-2.4)%, precision for inter-assay and intra-assay was <10 % and 6 %, respectively.p><p>CONCLUSIONThe HPLC method established is simple, accurate and suitable for the determination of amlodipine in cytochrome p450 cDNA-expressed cells.p>
Amlodipine ; analysis ; metabolism ; Calcium Channel Blockers ; analysis ; Chromatography, High Pressure Liquid ; Cytochrome P-450 CYP3A ; Cytochrome P-450 Enzyme System ; genetics ; physiology ; Humans ; Transfection

<p>OBJECTIVEThe cytochrome P450 subfamily IIIA5 (CYP3A5) gene is responsible for the metabolism of many clinically used anticancer agents. So far the studies on CYP3A5 gene has only been focused on the leukemia cell lines. This study examined the polymorphism of CYP3A5 and tried to find the possible relationship between CYP3A5 gene expression and treatment outcome or prognosis in children with acute leukemia.p><p>METHODSThe genotype distribution of CYP3A5-6986A/G gene polymorphism was detected with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 66 children with newly diagnosed acute leukemia (AL) and 22 control individuals. Quantitative real-time RT-PCR was used to examine wt-CYP3A5 and SV1-CYP3A5 mRNA levels in the bone marrow.p><p>RESULTSThree genotypes of CYP3A5-6986A/G polymorphisms were found: CYP3A5*1/*1, CYP3A5*1/*3 and CYP3A5*3/*3. There were significant differences in the wt-CYP3A5 mRNA expression among the AL patients with different genotypes (p<0.05). In patients with acute lymphocytic leukaemia (ALL), the complete remission (CR) rate in the group with a low expression of wt-CYP3A5 mRNA was significantly higher than that in the group with a high expression (p<0.05). A dynamic monitoring for wt-CYP3A5 mRNA expression was performed in two cases of ALL. The expression increased before ALL relapse compared with that in CR in a patient, while in the other patient, the expression was kept in a low level and the patient remained in CR CONCLUSIONS: wt-CYP3A5 mRNA expression was associated with the treatment outcome and prognosis in children with AL. Dynamic monitoring for wt-CYP3A5 mRNA expression in the bone marrow may be useful in the evaluation of the disease severity in childhood acute leukemia.p>
Acute Disease ; Child ; Cytochrome P-450 CYP3A ; genetics ; Genotype ; Humans ; Leukemia ; enzymology ; genetics ; Polymerase Chain Reaction ; RNA, Messenger ; analysis

<p>OBJECTIVETo screen a group of traditional Chinese medicines with effect on pregnane X receptor (PXR)-mediated transcription regulation of P450 3A4 (CYP3A4); and to study whether they can induce the expression of CYP3A4 with a dose, time-dependent manner.p><p>METHODTransient cotransfection reporter gene assays were performed with pCI-hPXR-neo, pGL3-CYP3A4-Luc and beta-galactosidase expression plasmid in HepG2 cells.p><p>RESULTRhizoma Curcumae, Atractylodes lancea, A. macrocaphala and Poria cocos could induce transcriptional expression of CYP3A4. In the dose-effect study, 24 h after induction, 500 mg x L(-1) Rhizoma Curcumae, A. lancea, A. macrocaphala and Poria cocos, respectively, could induce the CYP3A4 gene expression with (6.82 +/- 0.09), (6.76 +/- 0.20), (5.49 +/- 0.13) and (4.97 +/- 0.07) folds, as compared with 0.1% DMSO treated cells. In the time-effect study, 500 mg x L(-1) Rhizoma curcumae, A. lancea, A. macrocaphala and Poria cocos for 48 h could induce the CYP3A4 gene expression with (7.74 +/- 0.54), (7.34 +/- 0.10), (5.54 +/- 0.11) and (5.32 +/- 0.18) folds, compared with 0.1% DMSO treated cells.p><p>CONCLUSIONRhizoma Curcumae, A. lancea, A. macrocaphala and Poria cocos could induce the expression of CYP3A4 gene transcription through activating PXR.p>
Cell Line, Tumor ; Cytochrome P-450 CYP3A ; genetics ; Drugs, Chinese Herbal ; pharmacology ; Humans ; Receptors, Steroid ; metabolism ; Transcription, Genetic ; drug effects

<p>OBJECTIVETo study the inhibitory effect of total saponins of the root and rhizome of Panax notoginseng (PNS) on drug metabolism enzyme CYP3A in rat livers and its kinetic analysis.p><p>METHODMicrosome enzyme was prepared by differential velocity centrifugation. Michaelis constant (Km) and maximum velocity (Vmax) of CYP3A, 50% inhibitory concentration of PNS on CYP3A, and the inhibition type and the inhibition constant of CYP3A (Ki, Kis) of PNS on CYP3A were calculated by Lineweaver-Burk and the low of semi-effect-probit.p><p>RESULTTotal saponins of the root and rhizome of panax notoginseng inhibited CYP3A activity, with IC50 of 689.54 mg x L(-1). Compared with the substrate aminopyrine, CYP3A showed Km of 0.036 mmol x L(-1) and Vmax of 21.01 micromol min(-1) x g(-1). Total saponins of the root and rhizome of panax notoginseng showed a mixed inhibition on CYP3A, with the inhibition constants of 247.79 mg x L(-1) (Ki) and 321.79 mg x L(-1) (Kis).p><p>CONCLUSIONTotal saponins of the root and rhizome of panax notoginseng have a significant effect on CYP3A activity in rat livers.p>
Animals ; Cytochrome P-450 CYP3A ; chemistry ; genetics ; metabolism ; Cytochrome P-450 CYP3A Inhibitors ; Enzyme Inhibitors ; chemistry ; pharmacology ; Kinetics ; Liver ; chemistry ; drug effects ; enzymology ; Male ; Panax notoginseng ; chemistry ; Rats ; Rats, Sprague-Dawley ; Rhizome ; chemistry ; Saponins ; chemistry ; pharmacology