Induction of cytochrome P450 2E1 expression in rat and gerbil astrocytes by inflammatory factors and ischemic injury.
Hepatic cytochromes P450 are known to be down-regulated by cytokines, lipopolysaccharide, Gram-positive bacteria, and viruses. Little is known, however, about the regulation by inflammation of cytochromes P450 in other tissues. We have found that lipopolysaccharide and interleukin-1 beta stimulate the expression of catalytically active CYP2E1 (but not CYP1A1 or CYP2B) up to 7-fold in rat brain primary cortical glial cultures. The induction reached a maximum after 24 hr and was accompanied by an increase in CYP2E1 mRNA. Chlormethiazole, a specific inhibitor of hepatic CYP2E1 transcription, completely inhibited the induction of CYP2E1 at the mRNA and enzyme levels. Immunofluorescence studies showed CYP2E1 to be expressed in a subset of astrocytes in the lipopolysaccharide-stimulated cortical glial cultures. Using a model of global ischemic injury in the gerbil, we found CYP2E1 to be induced in vivo in astrocytes in the inflammatory phase, 1-3 weeks after the lesion. Likewise, CYP2E1 was induced in the rat cortex 1 week after a focal ischemic injury. Our results suggest tissue-specific regulation of CYP2E1 by inflammatory factors and that CYP2E1 may play a role in astrocytes during inflammation in the brain.
Department of Medical Biochemistry and Biophysics, Karolinska institute, Stockholm, Sweden.
N
N
Tindberg
H A
HA
Baldwin
A J
AJ
Cross
M
M
Ingelman-Sundberg
D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D002545:Brain Ischemia / Q000201:enzymology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology*; D002719:Chlormethiazole / Q000494:pharmacology; D002753:Chlorzoxazone / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis*; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005849:Gerbillinae; D006900:Hydroxylation; D007249:Inflammation / Q000201:enzymology*; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D002719:Chlormethiazole; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone