Effect of ivermectin on activities of cytochrome P450 isoenzymes in mouflon (Ovis musimon) and fallow deer (Dama dama)

Ivermectin is an antiparasitic drug widely used in veterinary and human med icine. We have found earlier that repeated treatments of rats with high dos es of this drug led to significant increase of cytochrome P450-dependent 7- methoxyresorufin O-demethylase (MROD) and 7-ethoxyresorufin O-deethylase (E ROD) activities in hepatic microsomes. In the present study, the effects of ivermectin on cytochrome P450 (CYP) activities were investigated in mouflo n (Oris musimon) and fallow deer (Dama dama). This study was conducted also to point out general lack of information on both basal levels of CYP enzym es and their inducibilities by veterinary drugs in wild ruminants. Liver mi crosomes were prepared from control animals, mourfions, after single or rep eated (six doses in six consecutive days) treatments with therapeutic (lose s of ivermectin 0.5 mg kg(1) of body weight), and fallow deer exposed to re peated doses of ivermectin under the same conditions. Alkyloxyre-sorufins. testosterone and chlorzoxazone were used as the specific substrate probes o r activities of the CYP isoenzymes. A single therapeutic dose of ivermectin significantly induced (300-400%,, of the control group) the activities of all alkyloxyresorufin dealkylases tested in mouflon liver microsomes. Repea ted doses of ivermectin also Caused in increase of these activities, but du e to fair inter-individual differences. this increase was not significant. The administration of ivermectin led to all induction (170-210% of the cont rol) of the testosterone 6 beta- and 16 alpha -hydroxylase activities in mo uflon liver but no significant modulation of chlorzoxazone hydroxylase (CZX OH) activity was found in mouflon liver. CYP-dependent activities in hepati c microsomes were generally higher in fallow deer than ill mouflons. Howeve r, with the exception or slight increase in the 7-benzyloxyresorufin O-deal kylase (BROD) activities, no significant modulation of the other activities was observed. The induction of CYP3A-like isoenzyme was confirmed by immun oblotting only in the microsomes from mouflons administered with repeated d oses of ivermectin: however. no significant increase of CYP1A isoenzymes wa s observed due to a weak cross-reactivity of anti-rat CYP1A1/2 polyclonal a ntibodies used in the study. The results indicate that ivermectin should be considered as an inducer of several cytochrome P450 isoenzymes, including CYP1A, 2B and 3A subfamilies, in mouflons. The comparison or induction effe ct of ivermectin in rat, mouflon and fallow deer also demonstrates the inte r-species differences in inducibility of CYP enzymes. (C) 2001 Elsevier Sci ence Ireland Ltd. All rights reserved.