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1.
Free Radic Res ; 52(9): 961-969, 2018 Sep.
Article in English | MEDLINE | ID: mdl-30422023

ABSTRACT

Emerging evidence suggests that microbial pathogens may induce oxidative stress in infected hosts. The aim of the present study was to investigate the relationship between changes in oxidative stress and intestinal infection with and without antibiotic treatment in animal models. Sprague-Dawley (SD) rats were divided into three groups: rats infected with Salmonella enterica serovar Enteritidis (S. enteritidis), rats infected with S. enteritidis followed by norfloxacin treatment, and the control group. To evaluate oxidative stress changes, levels of 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn) and 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxo-dGsn), which represented oxidative damage to RNA and DNA, respectively, were analysed in urine and tissue samples. In urine, the level of 8-oxo-Gsn increased significantly after oral exposure to S. enteritidis (p ≤ 0.001) and returned to baseline after recovery. Notably, norfloxacin treatment decreased the level of 8-oxo-Gsn in urine significantly (p = 0.001). Changes of 8-oxo-Gsn measured in tissues from the small intestine, colon, liver and spleen were consistent with 8-oxo-Gsn measured in urine. Our study suggested that 8-oxo-Gsn in urine may serve as a highly sensitive biomarker for evaluating the severity of S. enteritidis infection and the effectiveness of antibiotic treatment against infection.


Subject(s)
DNA Damage/drug effects , Infections/genetics , Liver/metabolism , Oxidative Stress , Animals , DNA Damage/genetics , Humans , Infections/microbiology , Infections/pathology , Intestinal Mucosa/microbiology , Intestinal Mucosa/pathology , Liver/microbiology , Liver/pathology , Oxidation-Reduction , Predictive Value of Tests , RNA/chemistry , Rats , Salmonella enteritidis/pathogenicity
2.
Oxid Med Cell Longev ; 2017: 2353729, 2017.
Article in English | MEDLINE | ID: mdl-29201270

ABSTRACT

To evaluate RNA oxidation in the early stage of diabetic nephropathy, we applied an accurate method based on isotope dilution high-performance liquid chromatography-triple quadruple mass spectrometry to analyze the oxidatively generated guanine nucleosides in renal tissue and urine from db/db mice of different ages. We further investigated the relationship between these oxidative stress markers, microalbumin excretion, and histological changes. We found that the levels of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) were increased in the urine and renal tissue of db/db mice and db/db mice with early symptoms of diabetic nephropathy suffered from more extensive oxidative damage than lean littermate control db/m mice. Importantly, in contrast to the findings in db/m mice, the 8-oxoGuo levels in the urine and renal tissue of db/db mice were higher than those of 8-oxodGuo at four weeks. These results indicate that RNA oxidation is more apparent than DNA oxidation in the early stage of diabetic nephropathy. RNA oxidation may provide new insight into the pathogenesis of diabetic nephropathy, and urinary 8-oxoGuo may represent a novel, noninvasive, and easily detected biomarker of diabetic kidney diseases if further study could clarify its source and confirm these results in a large population study.


Subject(s)
Diabetic Nephropathies/pathology , Oxidative Stress , RNA/metabolism , 8-Hydroxy-2'-Deoxyguanosine , Animals , Biomarkers/analysis , Biomarkers/urine , Blood Glucose/analysis , Chromatography, High Pressure Liquid , DNA/chemistry , DNA/metabolism , DNA Damage , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/analysis , Deoxyguanosine/urine , Diabetic Nephropathies/metabolism , Guanosine/analogs & derivatives , Guanosine/analysis , Guanosine/urine , Kidney/metabolism , Kidney/pathology , Mice , Mice, Obese , Oxidation-Reduction , RNA/chemistry , Spectrophotometry, Ultraviolet , Tandem Mass Spectrometry
3.
Free Radic Res ; 49(10): 1199-209, 2015 Oct.
Article in English | MEDLINE | ID: mdl-25968952

ABSTRACT

We used a sensitive and accurate method based on isotope dilution high-performance liquid chromatography-triple quadrupole mass spectrometry (ID-LC-MS/MS) to determine the levels of 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxo-dGsn) and 8-oxo-7,8-dihydroguanosin (8-oxo-Gsn) in various tissue specimens, plasma, and urine of hyperglycemic Sprague Dawley rats induced by streptozotocin (STZ). The oxidative DNA and RNA damages were observed in various organs and the amounts of 8-oxo-dGsn and 8-oxo-Gsn derived from DNA and RNA were increased with hyperglycemic status. In contrast to the results of the nucleic acid samples derived from tissues, the levels of 8-oxo-Gsn in urine and plasma were significantly higher compared with that of 8-oxo-dGsn, which most likely reflected the RNA damage that occurs more frequently compared with DNA damage. For the oxidative stress induced by hyperglycemia, 8-oxo-Gsn in urine may be a sensitive biomarker on the basis of the results in urine, plasma, and tissues. In addition, high levels of urinary 8-oxo-Gsn were observed before diabetic microvascular complications. Based on that the 8-oxo-dGsn was associated with diabetic nephropathy and RNA was more vulnerable to oxidative stress compared with DNA. We also propose that 8-oxo-Gsn is correlated with diabetic nephropathy and that 8-oxo-Gsn in urine could be a useful and sensitive marker of diabetic nephropathy.


Subject(s)
DNA Damage , DNA/metabolism , Diabetes Mellitus, Experimental/metabolism , Diabetic Nephropathies/metabolism , Hyperglycemia/metabolism , RNA/metabolism , Animals , Biomarkers , Chromatography, High Pressure Liquid , Diabetes Mellitus, Experimental/genetics , Diabetic Nephropathies/genetics , Guanine/analogs & derivatives , Guanine/analysis , Hyperglycemia/genetics , Mass Spectrometry , Oxidative Stress , Random Allocation , Rats , Rats, Sprague-Dawley , Streptozocin , Time Factors
4.
Biomed Res Int ; 2015: 368976, 2015.
Article in English | MEDLINE | ID: mdl-25629045

ABSTRACT

The objective of this work was to investigate the effect of orally administered genistein on the pharmacokinetics of imatinib and N-desmethyl imatinib in rats. Twenty-five healthy male SD (Sprague-Dawley) rats were randomly divided into five groups: A group (control group), B group (multiple dose of 100 mg/kg genistein for consecutive 15 days), C group (multiple dose of 50 mg/kg genistein for consecutive 15 days), D group (a single dose of 100 mg/kg genistein), and E group (a single dose of 50 mg/kg genistein). A single dose of imatinib is administered orally 30 min after administration of genistein (100 mg/kg or 50 mg/kg). The pharmacokinetic parameters of imatinib and N-desmethyl imatinib were calculated by DAS 3.0 software. The multiple dose of 100 mg/kg or 50 mg/kg genistein significantly (P < 0.05) decreased the AUC0-t and C max of imatinib. AUC0-t and the C max of N-desmethyl imatinib were also increased, but without any significant difference. However, the single dose of 100 mg/kg or 50 mg/kg genistein has no effect on the pharmacokinetics of imatinib and N-desmethyl imatinib. Those results indicated that multiple dose of genistein (100 mg/kg or 50 mg/kg) induces the metabolism of imatinib, while single dose of genistein has no effect.


Subject(s)
Benzamides/pharmacokinetics , Genistein/pharmacokinetics , Piperazines/pharmacokinetics , Pyrimidines/pharmacokinetics , Animals , Benzamides/administration & dosage , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Genistein/administration & dosage , Imatinib Mesylate , Male , Mass Spectrometry , Piperazines/administration & dosage , Pyrimidines/administration & dosage , Rats, Sprague-Dawley , Time Factors
5.
Drug Dev Ind Pharm ; 41(8): 1363-7, 2015.
Article in English | MEDLINE | ID: mdl-25144335

ABSTRACT

CYP2C9 is an important member of the cytochrome P450 enzyme superfamily, and 57 cytochrome P450 2C9 alleles have been previously reported. To examine the enzymatic activity of the CYP2C9 alleles, kinetic parameters for 4'-hydroxyflurbiprofen were determined using recombinant human P450s CYP2C9 microsomes from insect cells Sf21 carrying wild-type CYP2C9*1 and other variants. The results showed that the enzyme activity of most of the variants decreased comparing with the wild type as the previous studies reported, while the enzyme activity of some of them increased, which were not in accordance with the previous researches. Of the 36 tested CYP2C9 allelic isoforms, two variants (CYP2C9*53 and CYP2C9*56) showed a higher intrinsic clearance value than the wild-type protein, especially for CYP2C9*56, exhibited much higher intrinsic clearance (197.3%) relative to wild-type CYP2C9*1, while the remaining 33 CYP2C9 allelic isoforms exhibited significantly decreased clearance values (from 0.6 to 83.8%) compared to CYP2C9*1. This study provided the most comprehensive data on the enzymatic activities of all reported CYP2C9 variants in the Chinese population with regard to the commonly used non-steroidal anti-inflammatory drug, flurbiprofen (FP). The results indicated that most of the tested rare alleles decreased the catalytic activity of CYP2C9 variants toward FP hydroxylation in vitro. This is the first report of all these rare alleles for FP metabolism providing fundamental data for further clinical studies on CYP2C9 alleles for FP metabolism in vivo.


Subject(s)
Cytochrome P-450 CYP2C9/genetics , Cytochrome P-450 CYP2C9/metabolism , Flurbiprofen/metabolism , Polymorphism, Genetic/physiology , Animals , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Humans , Insecta
6.
Drug Dev Ind Pharm ; 41(4): 613-6, 2015 Apr.
Article in English | MEDLINE | ID: mdl-24517573

ABSTRACT

Cytochrome P450 2C9 (CYP2C9), one of the most important phase I drug metabolizing enzymes, could catalyze the reactions that convert diclofenanc into diclofenac 4'-hydroxylation. Evaluation of the inhibitory effects of compounds on CYP2C9 is clinically important because inhibition of CYP2C9 could result in serious drug-drug interactions. The objective of this work was to investigate the effects of curcumin on CYP2C9 in human and cytochrome P450 2C11 (CYP2C11) in rat liver microsomes. The results showed that curcumin inhibited CYP2C9 activity (10 µmol L(-1) diclofenac) with half-maximal inhibition or a half-maximal inhibitory concentration (IC50) of 15.25 µmol L(-1) and Ki = 4.473 µmol L(-1) in human liver microsomes. Curcumin's mode of action on CYP2C9 activity was noncompetitive for the substrate diclofenanc and uncompetitive for the cofactor NADPH. In contrast to its potent inhibition of CYP2C9 in human, diclofenanc had lesser effects on CYP2C11 in rat, with an IC50 ≥100 µmol L(-1). The observations imply that curcumin has the inhibitory effects on CYP2C9 activity in human. These in vitro findings suggest that more attention should be paid to special clinical caution when intake of curcumin combined with other drugs in treatment.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors , Curcumin/adverse effects , Cytochrome P-450 CYP2C9/metabolism , Cytochrome P-450 Enzyme Inhibitors/adverse effects , Dietary Supplements/adverse effects , Microsomes, Liver/enzymology , Steroid 16-alpha-Hydroxylase/antagonists & inhibitors , Animals , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Agents, Phytogenic/metabolism , Antioxidants/adverse effects , Antioxidants/metabolism , Aryl Hydrocarbon Hydroxylases/metabolism , Curcumin/metabolism , Cytochrome P-450 CYP2C9/chemistry , Cytochrome P-450 CYP2C9 Inhibitors/adverse effects , Cytochrome P-450 CYP2C9 Inhibitors/metabolism , Cytochrome P-450 Enzyme Inhibitors/metabolism , Cytochrome P450 Family 2 , Diclofenac/metabolism , Food-Drug Interactions , Humans , Kinetics , Male , Metabolic Detoxication, Phase I , Microsomes, Liver/metabolism , NADP/metabolism , Rats, Sprague-Dawley , Species Specificity , Steroid 16-alpha-Hydroxylase/metabolism
7.
Can J Physiol Pharmacol ; 92(11): 961-4, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25365188

ABSTRACT

The objective of this work was to investigate the effect of orally administered silybin on the pharmacokinetics of imatinib in rats and the metabolism of imatinib in human liver microsome and rat liver microsomes. Eighteen healthy male SD rats were randomly divided into 3 groups: group A (control group), group B (received multiple doses of 50 mg·kg(-1) silybin for 15 consecutive days), and group C (received a single dose of 50 mg·kg(-1) silybin). A single dose of imatinib was administered orally 30 min after administration of silybin (50 mg·kg(-1)). Imatinib plasma levels were measured by UPLC-MS/MS, and pharmacokinetic parameters were calculated by DAS 3.0 software (Bontz Inc., Beijing, China). In addition, human and rat liver microsome were performed to determine the effects of silybin metabolism of imatinib in vitro. The multiple doses or single dose of 50 mg·kg(-1) silybin significantly decreased the area under the curve (0-t) of imatinib (p < 0.01). And the half-life (t1/2) of imatinib is significantly increased (p < 0.05 and p < 0.01, respectively). Also, silybin showed inhibitory effect on human and rat microsomes, the IC50 of silybin were 26.42 µmol·L(-1) and 49.12 µmol·L(-1) in human and rat liver microsomes, respectively. These results indicate that more attention should be paid to when imatinib is administrated combined with silybin.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Antioxidants/pharmacology , Benzamides/pharmacokinetics , Piperazines/pharmacokinetics , Pyrimidines/pharmacokinetics , Silymarin/pharmacology , Animals , Humans , Imatinib Mesylate , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Rats, Sprague-Dawley , Silybin
8.
Pharmazie ; 69(12): 898-903, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25951663

ABSTRACT

CYP2C9 is one of four known members of the human cytochrome P450 CYP2C superfamily, with at least 57 CYP2C9 alleles being previously identified. Genetic polymorphisms of CYP2C9 significantly influence the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. The purpose of the present study was to clarify the role of 36 CYP2C9 alleles, 21 novel alleles (*36-*56) found in the Chinese population, in the oxidative metabolism of diclofenac in vitro. Insect microsomes expressing the 36 human CYP2C9 alleles were incubated with 2-100 µM diclofenac for 30 min at 37 degrees C and terminated by the addition of 30 µL 0.1 M HCl. Diclofenac and 4'-hydroxyl (OH)-diclofenac, the major diclofenac metabolite, were analyzed by high-performance liquid chromatography (HPLC). Compared with wild-type CYP2C9*1, most variants showed significantly altered values in V(max), K(m) and intrinsic clearance (V(max)/K(m)). Only one variant exhibited markedly increased intrinsic clearance value, whereas 31 variants exhibited significantly decreased values. Thus, this study demonstrated that more attention should be given to subjects carrying these CYP2C9 alleles when administering diclofena.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Cytochrome P-450 CYP2C9/genetics , Cytochrome P-450 CYP2C9/metabolism , Diclofenac/pharmacokinetics , Animals , Cell Line , Humans , Insecta/metabolism , Kinetics , Oxidation-Reduction , Polymorphism, Genetic/genetics , Recombinant Proteins/metabolism
9.
Biomed Res Int ; 2013: 789184, 2013.
Article in English | MEDLINE | ID: mdl-24369535

ABSTRACT

The purpose of this study was to determine the effect of apigenin on the pharmacokinetics of imatinib and N-desmethyl imatinib in rats. Healthy male SD rats were randomly divided into four groups: A group (the control group), B group (the long-term administration of 165 mg/kg apigenin for 15 days), C group (a single dose of 165 mg/kg apigenin), and D group (a single dose of 252 mg/kg apigenin). The serum concentrations of imatinib and N-desmethyl imatinib were measured by HPLC, and pharmacokinetic parameters were calculated using DAS 3.0 software. The parameters of AUC(0-t), AUC(0-∞), Tmax, V(z)/F, and CL(z)/F for imatinib in group B were different from those in group A (P < 0.05). Besides, MRT(0-t) and MRT(0-∞) in groups C and D differed distinctly from those in group A as well. The parameters of AUC(0-t) and Cmax for N-desmethyl imatinib in group C were significantly lower than those in group A (P < 0.05); however, compared with groups B and D, the magnitude of effect was modest. Those results indicated that apigenin in the short-term study inhibited the metabolism of imatinib and its metabolite N-desmethyl imatinib, while in the long-term study the metabolism could be accelerated.


Subject(s)
Apigenin/administration & dosage , Benzamides/metabolism , Benzamides/pharmacokinetics , Piperazines/metabolism , Piperazines/pharmacokinetics , Pyrimidines/metabolism , Pyrimidines/pharmacokinetics , Animals , Benzamides/antagonists & inhibitors , Benzamides/blood , Chromatography, High Pressure Liquid , Humans , Imatinib Mesylate , Piperazines/antagonists & inhibitors , Piperazines/blood , Pyrimidines/antagonists & inhibitors , Pyrimidines/blood , Rats
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