CYTOCHROME-P-450 COMPLEX-FORMATION IN RAT-LIVER BY THE ANTIBIOTIC TIAMULIN

Tiamulin is a semisynthetic diterpene antibiotic frequently used in fa rm animals, The drug has been shown to produce clinically important-of ten lethal-interactions with other compounds, It has been suggested th at this is caused by a selective inhibition of oxidative drug metaboli sm via the formation of a cytochrome P-450 metabolic intermediate comp lex, In the present study, rats were treated orally for 6 days with ti amulin at two different doses: 40 and 226 mg/kg of body weight. For co mparison, another group received 300 mg of triacetyloleandomycin (TAO) per kg, which is equivalent to the 226-mg/kg tiamulin group, Subseque ntly, microsomal P-450 contents, P-450 enzyme activities, metabolic in termediate complex spectra, and P-450 apoprotein concentrations were a ssessed, In addition, effects on individual microsomal P-450 activitie s were studied in control microsomes at different tiamulin and substra te concentrations, In the rats treated with tiamulin, a dose-dependent complex formation as evidenced by its absorption spectrum and an incr ease in cytochrome P-4503A1/2 contents as assessed by Western blotting (immunoblotting) were found, The effects were comparable to those of TAO, Tiamulin induced microsomal P-450 content, testosterone 6 beta-hy droxylation rate! erythromycin N-demethylation rate, and the ethoxyres orufin O-deethylation activity, Other activities were not affected or decreased, When tiamulin was added to microsomes of control rats, the testosterone 6 beta-hydroxylation rate and the erythromycin N-demethyl ation were strongly inhibited, It is concluded that tiamulin is a pote nt and selective inducer-inhibitor of cytochrome P-450, Though not bel onging to the macrolides, the compound produces an effect on P-450 sim ilar to those of TAO and related compounds.