INDUCTION OF HEPATIC CYTOCHROME-P450 2B AND P450 3A ISOZYMES IN RATS BY ZOLAZEPAM, A CONSTITUENT OF TELAZOL(R)

Telazol(R), a 1:1 combination of tiletamine HCl and zolazepam HCl, is an anesthetic and immobilizing agent that is capable of inducing cytoc hrome P450 (CYP) 2B isozymes in rats. The primary goal of the present study was to determine the constituent of Telazol(R) responsible for t he enzyme induction. A secondary goal was to compare the effects produ ced by Telazol(R) and its constituents with those elicited by sodium p henobarbital (PB) using the same dosing regimen. Adult male Long Evans rats were given a single i.p. injection of tiletamine or zolazepam at a dose of 60 mg/kg, Telazol(R) at a dose of 120 mg/kg, PB at a dose o f 60 and 120 mg/kg, or vehicle at a dose of 1 mL/kg. Animals were kill ed 24 hr later, and hepatic microsomes were prepared. Treatment with z olazepam and Telazol(R) increased microsomal benzyloxyresorufin O-deal kylase (BROD) activity by approximately 9- and 15-fold, respectively, and increased microsomal testosterone 16 beta-hydroxylase activity by 5- and 8-fold, respectively. Treatment with tiletamine had a slight, b ut insignificant, effect on CYP-mediated enzyme activities. In compari son, BROD and testosterone 16 beta-hydroxylase activities were increas ed by 22- and 13-fold, respectively, after treatment with PB at a dose of 60 mg/kg. Densitometric quantitation of immunoblots revealed that the hepatic CYP2B content was elevated by approximately 15-, 22-, and 25-fold, and the hepatic CYP3A content was increased by 2-, 2-, and 8- fold after treatment with zolazepam, Telazol(R), and PB, respectively. In contrast, levels of CYP1A1 and CYP2E1 were unaltered after treatme nt. In summary, the results indicate that zolazepam was the constituen t primarily responsible for the inductive effect of Telazol(R), and th e pattern of enzyme induction produced by zolazepam and Telazol(R) was similar to, but weaker than that elicited by PB at a similar dosing r egimen. (C) 1998 Elsevier Science Inc.