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Effects of Telazol®, Tiletamine, and Zolazepam on hepatic cytochrome P450 expresssion in rats

University of British Columbia

The goal of the present project was to examine the effects the immobilizing agent, Telazol® , and its constituents, tiletamine and zolazepam, on cytochrome P450 expression in rats. The effects elicited by the three agents were compared with those produced by phenobarbital (PB) using a similar dosing regimen. In the first of three sections, male Long Evans rats received a single i.p. injection of Telazol at a dose of 20, 40, 80, or 120 mg/kg. Rats were killed 24 h later and hepatic microsomes prepared. Treatment with Telazol® produced a dose-dependent increase in benzyloxyresorufin (BROD) and pentoxyresorufin (PROD) O-dealkylase, and testosterone 16β-hydroxylase activities. The same treatment group showed a significant increase of 17-fold in the hepatic level of cytochrome P450 2B1. A dose-dependent but insignificant increase was found in the hepatic level of cytochrome P450 2B2. In section 2, male Long Evans rats received a single i.p. injection of tiletamine at a dose of 60 mg/kg, zolazepam at a dose of 60 mg/kg, or Telazol® at a dose of 120 mg/kg. Rats were killed 24 h later and hepatic microsomes prepared. Tiletamine produced a small but insignificant increase in BROD and testosterone 16p-hydroxylase activities, whereas zolazepam and Telazol increased the enzyme activities by 4.7- to 15.3-fold, respectively. The lather treatments also significantly increased hepatic levels of cytochrome P450 2B1, P450 2B2, and P450 3A isozymes. In section 3, male Long Evans rats received a single i.p. injection of PB at a dose of 60 or 120 mg/kg. Rats were killed 24 h later and hepatic microsomes prepared. PB at a dose of 120 mg/kg increased BROD, EROD, and PROD activities by 22.6-, 2.0-, and 7.0-fold, respectively, while significant increases of 1.7-, 17.4-, and 1.7-fold, respectively, were found in the rates of formation of 6β-, 16β-hydroxytestosterone, and androstenedione. The same treatment elevated hepatic levels of cytochrome P450 2B and P450 3A isozymes by 24.9- and 8.9-fold, respectively. Treatment with PB at a dose of 60 mg/kg produced similar increases in enzyme activities and protein contents of cytochromes P450. In summary, results indicated that Telazol®, at a dose of 80 mg/kg or greater, induced hepatic expression of cytochrome P450 2B in rats. Zolazepam was the major constituent responsible for the enzyme induction. The pattern of induction produced by Telazol® was similar to that elicited by PB, although PB at a similar dose produced a greater inductive effect on cytochromes P450.

Thesis/Dissertation

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2009-02-17

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http://hdl.handle.net/2429/4667

Pharmaceutical Sciences

University of British Columbia

UBCV

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