Phenobarbital induces monkey brain CYP2E1 protein but not hepatic CYP2E1, in vitro or in vivo chlorzoxazone metabolism.
Cytochrome P450 2E1 (CYP2E1) is expressed in the brain and liver, and can metabolize clinical drugs and activate toxins. The effect of phenobarbital on hepatic and brain CYP2E1 is unclear. We investigated the effect of chronic phenobarbital treatment on in vivo chlorzoxazone disposition (a CYP2E1 probe drug), in vitro chlorzoxazone metabolism, and hepatic and brain CYP2E1 protein levels in African Green monkeys (Cercopithecus aethiops). Monkeys were given oral saccharine or saccharine supplemented with 20 mg/kg phenobarbital (N = 6/group) for 22 days. Phenobarbital did not induce in vivo chlorzoxazone disposition, in vitro chlorzoxazone metabolism or hepatic CYP2E1 protein levels (all P > 0.05). However, phenobarbital induced brain CYP2E1 protein levels, using immunoblotting, by 1.26-fold in the cerebellum (P = 0.01) and 1.46-fold in the putamen (P = 0.04). Phenobarbital also increased cell-specific CYP2E1 expression, for example in the frontal cortical pyramidal neurons and cerebellar Purkinje cells. This data indicates that phenobarbital does not alter hepatic metabolism, but may alter metabolism of CYP2E1 substrates within the brain.
Lee
Anna M
AM
The Centre for Addiction and Mental Health, and the Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.
Joshi
Meenal
M
Yue
Jiang
J
Tyndale
Rachel F
RF
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002522:Chlorocebus aethiops; D002753:Chlorzoxazone / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000494:pharmacology; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D010634:Phenobarbital / Q000008:administration & dosage / Q000494:pharmacology*
D006993:Hypnotics and Sedatives; C039289:6-hydroxychlorzoxazone; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone; D010634:Phenobarbital