Expression of constitutive and inducible cytochrome P450 2E1 in rat brain.
Studies initiated to investigate the expression of cytochrome P450 2E1 (CYP2E1) in rat brain demonstrated low but detectable protein and mRNA expression in control rat brain. Though mRNA and protein expression of CYP2E1 in brain was several fold lower as compared to liver, relatively high activity of N-nitrosodimethylamine demethylase (NDMA-d) was observed in control rat brain microsomes. Like liver, pretreatment with CYP2E1 inducers such as ethanol or pyrazole or acetone significantly increased the activity of brain microsomal NDMA-d. Kinetic studies also showed an increase in the Vmax and affinity (Km) of the substrate towards the brain enzyme due to increased expression of CYP2E1 in microsomes of brain isolated from ethanol pretreated rats. In vitro studies using organic inhibitors, specific for CYP2E1 and anti-CYP2E1 significantly inhibited the brain NDMA-d activity indicating that like liver, NDMA-d activity in rat brain is catalyzed by CYP2E1. Olfactory lobes exhibited the highest CYP2E1 expression and catalytic activity in control rats. Furthermore, several fold increase in the mRNA expression and activity of CYP2E1 in cerebellum and hippocampus while a relatively small increase in the olfactory lobes and no significant change in other brain regions following ethanol pretreatment have indicated that CYP2E1 induction maybe involved in selective sensitivity of these brain areas to ethanol induced free radical damage and neuronal degeneration.
Yadav
Sanjay
S
Industrial Toxicology Research Centre, P.O. Box 80, Mahatma Gandhi Marg, Lucknow 226 001, INDIA.
Dhawan
Alok
A
Singh
Ram L
RL
Seth
Prahlad K
PK
Parmar
Devendra
D
D000096:Acetone / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D002492:Central Nervous System Depressants / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002492:Central Nervous System Depressants; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D012333:RNA, Messenger; D000096:Acetone; D000431:Ethanol; C031280:pyrazole; D019392:Cytochrome P-450 CYP2E1