Τίτλος:
Hepatic drug metabolizing profile of Flinders Sensitive Line rat model of depression
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
The Flinders Sensitive Line (FSL) rat model of depression exhibits some behavioral, neurochemical, and pharmacological features that have been reported in depressed patients and has been very effective in screening antidepressants. Major factor that determines the effectiveness and toxicity of a drug is the drug metabolizing capacity of the liver. Therefore, in order to discriminate possible differentiation in the hepatic drug metabolism between FSL rats and Sprague-Dawley (SD) controls, their hepatic metabolic profile was investigated in this study. The data showed decreased glutathione (GSH) content and glutathione S-transferase (GST) activity and lower expression of certain major CYP enzymes, including the CYP2B1, CYP2C11 and CYP2D1 in FSL rats compared to SD controls. In contrast, p-nitrophenol hydroxylase (PNP), 7-ethoxyresorufin-O-dealkylase (EROD) and 16α-testosterone hydroxylase activities were higher in FSL rats. Interestingly, the wide spread environmental pollutant benzo(α)pyrene (B(α)P) induced CYP1A1, CYP1A2, CYP2B1/2 and ALDH3c at a lesser extend in FSL than in SD rats, whereas the antidepressant mirtazapine (MIRT) up-regulated CYP1A1/2, CYP2C11, CYP2D1, CYP2E1 and CYP3A1/2, mainly, in FSL rats. The drug also further increased ALDH3c whereas suppressed GSH content in B(α)P-exposed FSL rats. In conclusion, several key enzymes of the hepatic biotransformation machinery are differentially expressed in FSL than in SD rats, a condition that may influence the outcome of drug therapy. The MIRT-induced up-regulation of several drug-metabolizing enzymes indicates the critical role of antidepressant treatment that should be always taken into account in the designing of treatment and interpretation of insufficient pharmacotherapy or drug toxicity. © 2010 Elsevier Inc.
Συγγραφείς:
Kotsovolou, O.
Ingelman-Sundberg, M.
Lang, M.A.
Marselos, M.
Overstreet, D.H.
Papadopoulou-Daifoti, Z.
Johanson, I.
Fotopoulos, A.
Konstandi, M.
Περιοδικό:
Progress in Neuro-Psychopharmacology and Biological Psychiatry
Λέξεις-κλειδιά:
16alpha testosterone hydroxylase; 4 nitrophenol hydroxylase; 7 ethoxyresorufin o dealkylase; aldehyde dehydrogenase; benzo[a]pyrene; cytochrome P450 1A1; cytochrome P450 1A2; cytochrome P450 2B1; cytochrome P450 2B2; cytochrome P450 2C11; cytochrome P450 2D1; cytochrome P450 2E1; cytochrome P450 3A1; cytochrome P450 3A2; glutathione; glutathione transferase; liver enzyme; mirtazapine; oxygenase; unclassified drug; cytochrome P450; cytochrome P450 1A1; dopamine; glutathione; glutathione transferase; mianserin; mirtazapine; noradrenalin; tricyclic antidepressant agent, animal cell; animal experiment; animal tissue; article; controlled study; depression; drug metabolism; drug transformation; enzyme activity; enzyme induction; Flinders sensitive line rat; liver metabolism; male; nonhuman; protein expression; rat; rat strain; Sprague Dawley rat; strain difference; analogs and derivatives; analysis of variance; animal; comparative study; depression; disease model; drug effects; enzymology; high performance liquid chromatography; hypothalamus; liver; metabolism; Western blotting, Analysis of Variance; Animals; Antidepressive Agents, Tricyclic; Blotting, Western; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP1A1; Cytochrome P-450 Enzyme System; Depressive Disorder; Disease Models, Animal; Dopamine; Glutathione; Glutathione Transferase; Hypothalamus; Liver; Male; Mianserin; Norepinephrine; Rats; Rats, Sprague-Dawley, Analysis of Variance; Animals; Antidepressive Agents, Tricyclic; Blotting, Western; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP1A1; Cytochrome P-450 Enzyme System; Depressive Disorder; Disease Models, Animal; Dopamine; Glutathione; Glutathione Transferase; Hypothalamus; Liver; Male; Mianserin; Norepinephrine; Rats; Rats, Sprague-Dawley
DOI:
10.1016/j.pnpbp.2010.05.029
