Toxicological consequences of differential regulation of cytochrome p450 isoforms in rat brain regions by phenobarbital.
Cytochrome P4502B is an isoform of cytochrome P450 (P450) that is induced by the anticonvulsant drug phenobarbital. Here, we demonstrate the constitutive expression and predominant localization of CYP2B in neurons of rat brain. Administration of phenobarbital to rats resulted in selective induction of P450 levels in cortex and midbrain, while other regions were unaffected. Immunohistochemical localization of P4502B in brains of phenobarbital treated rats revealed localization of P4502B in neuronal cells, most predominantly the reticular neurons in midbrain. The anticancer agent 9-methoxy-N(2)-methylellipticinium acetate (MMEA) has been shown to exhibit preferential neuronal toxicity in vitro. Pretreatment of rats with phenobarbital potentiated the toxicity of intrathecally administered MMEA in vivo, as seen by the degeneration of reticular neurons. Thus, induction of P450 in selective regions of brain by phenobarbital would profoundly influence xenobiotic metabolism in these regions, especially in clinical situations where phenobarbital is coadministered with other psychoactive drugs/xenobiotics.
Upadhya
Sudarshan C
SC
National Brain Research Centre, Aruna Asaf Ali Marg, New Delhi, 110 067, India.
Chinta
Shankar J
SJ
Pai
Harish V
HV
Boyd
Michael R
MR
Ravindranath
Vijayalakshmi
V
D000429:Alcohol Oxidoreductases; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000633:toxicity; D001189:Aryl Hydrocarbon Hydroxylases; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D004611:Ellipticines / Q000633:toxicity; D015151:Immunoblotting; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008636:Mesencephalon / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis / Q000235:genetics; D010634:Phenobarbital / Q000494:pharmacology*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D015533:Transcriptional Activation
D000927:Anticonvulsants; D000970:Antineoplastic Agents; D004611:Ellipticines; D020033:Protein Isoforms; D012333:RNA, Messenger; C091664:9-methoxy-N(2)-methylellipticinium; D003577:Cytochrome P-450 Enzyme System; D000429:Alcohol Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; C504568:Cyp2d1 protein, rat; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D010089:Oxidoreductases, N-Demethylating; D010634:Phenobarbital