Evidence for O-dealkylation of 7-pentoxyresorufin by cytochrome P450 2B1/2B2 isoenzymes in brain.
O-dealkylation of 7-pentoxyresorufin (PR) was studied in rat brain to characterise the functional activity specific for cytochrome P450 2B1/2B2 isoenzymes in brain microsomes. Brain microsomes catalyzed the O-dealkylation of PR in the presence of NADPH. Pretreatment with phenobarbital (PB; 80 mg/kg body wt, i.p. x 5 days) resulted in 3-4 fold induction of pentoxyresorufin-O-dealkylase (PROD) activity while 3-methylcholanthrene (MC; 30 mg/kg body wt, i.p. x 5 days) did not produce any significant increase in enzyme activity. Kinetic studies revealed that the rate of velocity (Vmax) for the O-dealkylation of PR was significantly increased to 2.9 times higher in brain microsomes isolated from PB pretreated rats. In vitro studies using metyrapone, an inhibitor of P450 2B1/2B2 catalyzed reactions and antibody for hepatic PB inducible P450s (P450 2B1/2B2) significantly inhibited the activity of PROD in cerebral microsomes prepared from PB pretreated animals. These studies suggest that PB inducible isoenzymes of P450, i.e. P450 2B1/2B2 specifically catalyze the O-dealkylation of PR in brain microsomes.
Parmar
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Industrial Toxicology Research Centre, M.G. Marg, Lucknow, India.
Dhawan
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A
Seth
P K
PK
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001571:Benzoflavones / Q000378:metabolism; D001921:Brain / Q000201:enzymology*; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003640:Dealkylation; D007074:Immunoglobulin G / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D008748:Methylcholanthrene / Q000378:metabolism; D008797:Metyrapone / Q000378:metabolism; D010078:Oxazines / Q000378:metabolism*; D010634:Phenobarbital / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013250:Steroid Hydroxylases / Q000378:metabolism*
D001571:Benzoflavones; D007074:Immunoglobulin G; D010078:Oxazines; D008748:Methylcholanthrene; C011512:alpha-naphthoflavone; C044943:pentoxyresorufin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; C025619:steroid 16-beta-hydroxylase; D010634:Phenobarbital; D008797:Metyrapone