Drug metabolizing enzyme expression in rat choroid plexus: effects of in vivo xenobiotics treatment.
The presence of drug metabolizing enzymes in extrahepatic tissues such as the choroid plexus (CP) suggests that the CP, like the blood-brain barrier, affords a metabolic protection to the brain against xenobiotics. The CP, which is the principal site of formation of the cerebrospinal fluid (CSF), controls the exchange of many endogenous compounds and exogenous molecules between brain tissue and CSF. We present the changes in mRNA expression and enzymatic activities of UDP-glucuronosyltransferase, UGT1A6 isoform and NADPH-cytochrome P450 reductase, after in vitro treatment with xenobiotic molecules known to act in the liver as inducers or inhibitors of these drug metabolizing enzymes. Five study groups of male Sprague-Dawley rats were treated separately with 3-methylcholantrene (3-MC), phenobarbital (PB), dexamethasone (DEX), cyclosporine (CsA) or paraquat (PQ). Choroidal 1-naphthol glucuronidation activities were significantly induced by 3-MC and PQ administration (354 +/- 85 and 257 +/- 49 vs. 115 +/- 24 nmol/h per mg protein, in control group), whereas the other molecules were without effect. Accordingly, UGT1A6 mRNA expression, measured by RT-PCR, was 2.3-fold higher after 3-MC treatment and 2.1-fold higher after PQ administration. By contrast, reductase activities and mRNA expression remained unchanged in the isolated choroids plexus in these experimental conditions. We present for the first time evidences that the choroids plexus express transcripts for both UGT1A6 and NADPH-cytochrome P450 reductase, and their mRNA expression can be differently regulated by exogenous factors. These results emphasize that xenobiotics could modulate the biotransformation of exogenous and/or endogenous compounds in the choroids plexus, and underline the role of UGTs in the maintenance of brain homeostasis.
Gradinaru
Daniela
D
Department of Biochemistry, Faculty of Pharmacy, "Carol Davila" University of Medicine and Pharmacy, 6 Traian Vuia Street, 70183 Bucharest, Romania. danielagrdnr@yahoo.com
Minn
Anne-Laure
AL
Artur
Yves
Y
Minn
Alain
A
Heydel
Jean-Marie
JM
D000818:Animals; D002831:Choroid Plexus / Q000187:drug effects / Q000201:enzymology; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D014453:Glucuronosyltransferase / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009251:NADPH-Ferrihemoprotein Reductase / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015262:Xenobiotics / Q000378:metabolism / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D015262:Xenobiotics; D009251:NADPH-Ferrihemoprotein Reductase; C110655:UDP-glucuronosyltransferase, UGT1A6; D014453:Glucuronosyltransferase