The role of stress in the regulation of drug metabolizing enzymes in mice.
The role of stress in the regulation of several enzymatic systems which are involved in the biotransformation of xenobiotics in the liver was investigated in this study using restraint stress as a stress model. The results demonstrated that stress suppressed total basal P450 content (35%) and basal ethoxyresorufin 7-dealkylase (EROD) activity (33%), while slightly increasing basal methoxyresorufin 7-dealkylase (MROD) activity (20%). Basal pentoxyresorufin 7- dealkylase (PROD) and coumarin 7-hydroxylase (COH) activities were not affected. On the other hand, restraint stress increased total P450 content in 1,4-bis[2-(3,5- dichloropyridyloxy)]benzene (TCPOBOP)-treated mice (35%), while slightly suppressing PROD activity (26%). In addition, CYP2E1 dependent p-nitrophenol hydroxylation (PNP), was suppressed (40%) by stress in TCPOBOP-treated animals and cytosolic aldehyde dehydrogenases were not affected. Although stress had no effect on basal P4502A5 activity, the inducibility of this hepatic activity increased 2-fold after stress exposure. A pronounced suppression (7-fold) in glutathione content was observed in lungs of TCPOBOP treated mice after stress, whereas basal levels remained unaffected. In addition, only a slight suppression (20%) in liver glutathione content was found in both treatment groups. Northern blot analysis revealed that restraint stress had a relatively suppressive effect on control CYP1A2 expression in the liver. In contrast, stress markedly enhanced the expression of liver CYP2A5 in TCPOBOP-treated mice, but did so to a lesser extent in controls. Stress also increased CYP2A5 mRNA in TCPOBOP-treated mice to a greater degree than the activity of the corresponding cytochrome. On the other hand, liver P4502A5 activity was found to be induced by TCPOBOP by about 2.5-fold. However, the drug does not appear to be involved in the expression of CYP2A5. Finally, although the activity of liver P4502A5 cytochrome was found to be increased 3, 8 and 27 h after stress, after which it gradually declined up to 75 h, CYP2A5 liver expression appeared to be suppressed 3, 8, 27 and 51 h after stress, while 75 h later it apparently reached normal levels. In conclusion, the results of this study showed that restraint stress significantly alters several enzymatic systems differently at a basal level than under conditions of TCPOBOP induction. In addition, stress was found to significantly interfere with the expression processes of CYP1A2 and CYP2A5.
D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D015152:Blotting, Northern; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006900:Hydroxylation / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D009596:Nitrophenols / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013315:Stress, Psychological / Q000503:physiopathology*; D013997:Time Factors