Effect of toluidines and dinitrotoluenes on caffeine metabolic ratio in rat

Caffeine (1,3,7-trimethylxanthine, CA) is metabolised by N-demethylation to three primary metabolites: theophylline (TP), paraxanthine (PX) and theobr omine (TB). This process is mediated in 95% by CYP1A2. Thus the measurement of CA demethylated metabolites can be used as a marker of CYP1A2 activity in vivo. In the present study, caffeine and its primary metabolites were de termined simultaneously in plasma of rats pretreated with three isomers of toluidine at doses: 1, 10, 60 mg/kg b.w., p.o. and four isomers of dinitrot oluene (DNT) at doses: 100 and 200 mg/kg b.w., p.o. Caffeine metabolite rat ios in plasma: TB/CA, PX/CA, TP/CA, TB+PX+TP/CA were calculated and compare d to those of control rats. Administration of toluidines resulted in a 2-20 fold increase of the concentration ratios of metabolites to caffeine. All toluidines seem to be inducers of CYP1A2. To the best of our knowledge this is the first information concerning the effect of toluidines on caffeine m etabolism. Two out of the four tested dinitrotoluenes slightly affected CYP 1A2 activity; 2,3- and 3,4-DNT increased estimated parameters 2-6 fold. Two others, 2,4- and 2,6-DNT can be considered as moderate hepatotoxic agents decreasing CA metabolic ratios to 4-70% of the control values. (C) 1999 Els evier Science Ireland Ltd. All rights reserved.