Characterization of the induction of rat microsomal cytochrome P450 by tacrine.
The effect of multiple-dose tacrine (THA) administration at 2 and 20 mg/kg (single oral doses for 2 weeks) on cytochrome P450 (CYP) was examined in male and female Wistar rats. Changes in CYP were determined by measuring total spectral CYP, the rates of ethoxy- and pentoxyresorufin dealkylations, and the protein expression of several CYPs by western blot analysis of liver microsomes. Animals treated with beta-naphthoflavone or phenobarbital were employed as positive controls. No physiological or metabolic changes were observed in male or female rats treated with 2 mg/kg THA for 2 weeks. Male and female animals treated with 20 mg/kg THA for 2 weeks demonstrated increased CYP1A activity (increased ethoxyresorufin deethylase activity) and increased expression of CYP1A1 with only minor increases in CYP1A2 expression. Compared with the effects of beta-naphthoflavone induction of CYP1A, the induction observed with THA at 20 mg/kg was considered minor.
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Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, MI 48105, U.S.A.
Woolf
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D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D001835:Body Weight; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D005260:Female; D007527:Isoenzymes / Q000096:biosynthesis*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013619:Tacrine / Q000008:administration & dosage*
D001571:Benzoflavones; D002800:Cholinesterase Inhibitors; D007527:Isoenzymes; D013619:Tacrine; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital