Hepatic drug metabolizing profile of Flinders Sensitive Line rat model of depression
Olga KotsovolouMagnus Ingelman‐SundbergMatti A. LangΜάριος ΜαρσέλοςDavid H. OverstreetZoi Papadopoulou-DaifotiInger JohansonAndrew D. FotopoulosMaria Konstandi
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Neurochemical
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Skatole
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[Objective] To examine the enzyme activities and protein expressions of liver CYP1A2 and CYP2E1 in rats exposed to organic extracts from drinking water, and to provide evidence for health risk assessment for local drinking water and elucidation of its hepatotoxicity. [Methods] Organic pollutants in drinking water were extracted by solid-phase extraction method. A total of 40 SD rats were randomly divided into four groups. The control group was administered with corn oil. The exposed groups were administered respectively with the organic extracts at 5, 20, and 80 L/(kg·d). The exposure by gavage lasted 12 weeks. Fluorescence spectrophotometry and chromatometry were applied to evaluate the activities of CYP1A2 and CYP2E1 respectively. The protein levels of CYP1A2 and CYP2E1 were measured by Western blot method. [Results] Compared with the control group, the enzyme activity of CYP1A2 in the 80 L/(kg·d) group increased remarkably(P 0.05); the enzyme activities of CYP2E1 in the 20 L/(kg·d) group and 80 L/(kg·d) group both increased significantly(P 0.05). With the rise of exposing dose, the expression of CYP1A2 protein significantly increased in the 80L/(kg·d) group(P 0.05). Compared with the control group, the expression of CYP2E1 protein obviously increased in the 20L/(kg·d) group and the 80 L/(kg·d) group(P 0.05). [Conclusion] Exposed to high level of organic extracts from the local drinking water could result in the up-regulated expressions of CYP1A2 and CYP2E1 proteins, and then induce the rise of CYP1A2 and CYP2E1 enzyme activities. This might be one of the important mechanisms for liver damage.
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Objective To explore the inhibitive effects of 1, 3, 8-trihydroxy-5-methoxyxanthone (TMX) on cytochrome P450s (CYP450s) in human liver microsomes. Methods Probe drugs were incubated with and without adding TMX to determine the changes of enzyme activities. The concentration ratio of metabolites to probe drugs was used to present enzyme activities. Concentrations of the probe drugs and their metabolites in the incubated mixture were detected by high performance liquid chromatography. Results The variations (mean, 95% CI) of the activities of CYP1A2, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 were 2.95×10^(-3) (2.03×10^(-3), 3.88×l0^(-3)), 3.14×10^(-2) (1.87×10^(-2), 4.42×10^(-2)), 2.27×10^(-3) (-1.4×10^(-2), 1.81×10^(-2)), 7.72×10^(-2) (-0.83×10^(-2), 0.2374), and -0.2548 (-2.9802, 2.4707), respectively. The activities of CP1A2 and CYP2C9 were significantly reduced in the present of TMX. Conclusion TMX (10μmol/L) has significant inhibitive effect on the activities of CYP1A2 and CYP2C9, but no significant inhibitive effect on the activities of CYP2C19, CYP2E1 and CYP3A4.
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Objective To explore the inhibitive effects of 1,3,8-trihydroxy-5-methoxyxanthone (TMX) on cytochrome P450s (CYP450s) in human liver microsomes. Methods Probe drugs were incubated with and without adding TMX to determine the changes of enzyme activities. The concentration ratio of metabolites to probe drugs was used to present enzyme activities. Concentrations of the probe drugs and their metabolites in the incubated mixture were detected by high performance liquid chromatography. Results The variations (mean, 95%CI) of the activities of CYP1A2, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 were 2.95 x 10(-3) (2.03 x 10(-3), 3.88 x 10(-3)), 3.14 x 10(-2) (1.87 x 10(-2), 4.42 x 10(-2)), 2.27 x 10(-3) (-1.4 x 10(-2),1.81 x 10(-2)), 7.72 x 10(-2) (-0.83 x 10(-2), 0.2374), and -0.2548 (-2.9802, 2.4707), respectively. The activities of CYP1A2 and CYP2C9 were significantly reduced in the present of TMX. Conclusion TMX (10 micromol/L) has significant inhibitive effect on the activities of CYP1A2 and CYP2C9, but no significant inhibitive effect on the activities of CYP2C19, CYP2E1 and CYP3A4.
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Objective To study the effect of Aconitum coadministration with ampelopsis on the enzyme activity,protein expression and mRNA level of cytochrome P450 isoenzymes in rat liver. Methods CYP1A2 and CYP2E1 activities were quantitated by high performance liquid chromatographic(HPLC) assay;CYP3A1/2 activity was quantitated by UV chromatography.The protein expressions of CYP1A2,CYP2E1,CYP3A1,and CYP3A2 were detected by Western blot.The mRNA levels of CYP1A2,CYP2E1,CYP3A1,and CYP3A2 were detected by semi-quantitative reverse transcriptase-polymerase chain reaction(RT-PCR). Results Aconitum coadministration with ampelopsis obviously inhibited the activities of CYP1A2,CYP2E1 and CYP3A1/2;Western Blot showed a decreased protein expression of CYP2E1,and CYP3A2,and an increased protein expression of CYP1A2 and CYP3A1.RT-PCR showed an increased mRNA level of CYP1A2,CYP2E1,CYP3A1,and CYP3A2 as compared with the control group. Conclusion Aconitum coadministration with ampelopsis has an inhibitory effect on the enzymes activity of CYP1A2,CYP2E1,and CYP3A1/2. The enzymes activity inhibitory effect of CYP2E1 may be related to the decrease of its protein expression,but not CYP1A2,CYP3A1,and CYP3A2.
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OBJECTIVE To study the effect of Aconitum with Fritillaria on the enzyme activity,protein expression and mRNA level of cytochrome P450 isoenzymes in rat liver.METHODS CYP1A2 and CYP2E1 activities were quantitated by high performance liquid chromatographic(HPLC)assay;CYP3A1/2 activity was determined by UV spectrophotometry.The protein expression of CYP1A2,CYP2E1,CYP3A1,and CYP3A2 were detected by Western blot.The mRNA level of CYP1A2,CYP2E1,CYP3A1,and CYP3A2 were detected by semi-quantitative reverse transcriptase-polymerase chain reaction(RT-PCR).RESULTS Aconitum administered with Fritillaria obviously inhibited the activities of CYP1A2,CYP2E1.The protein expression of CYP1A2,CYP2E1,and CYP3A2 were markedly inhibited when treated with Aconitum together with Fritillaria but the protein expression of CYP3A1 was increased.The mRNA level of CYP1A2 and CYP2E1 was decreased compared with control group,but the mRNA level of CYP3A1 and CYP3A2 were increased.CONCLUSION Aconitum administered with Fritillaria has an inhibitory effect on the enzyme activity of CYP1A2 and CYP2E1.The enzyme activity inhibitory effect may be caused via the decrease of CYP1A2 and CYP2E1 protein expression.
Aconitum
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To study the effects of salvianolic acid A on content of cytochrome P450,cytochrome b5 and CYP1A2, CYP2E1 activities of rats.The rats were randomly divided into two groups and each group contained 5 male rats and 5 female rats. One is control group, another is dosage group. The dosage group was injected salvianolic acid A into a rat tail vein at doses of 20 mg x kg(-1) x d(-1) for 5 days. The control group was injected placebo into a rat tail vein at the same doses as the dosage group. The content of cytochrome P450 and cytochrome b5 of rats were assayed using UV and CYP1A2, CYP2E1 activities were evaluated using probe substrate.After salvianolic acid A was injected into rats tail vein for 5 days, the total content of cytochrome P450 and cytochrome b5 and CYP1A2 and CYP2E1 activities have no statistical significance of differences than the control group.Salvianolic acid A has no effects on CYP1A2 and CYP2E1 activities, indicating that there is no internation between salvianolic acid A and the drugs metabolized by CYP1A2 or CYP2E1.
Cytochrome b5
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