CHARACTERIZATION OF RAT HEPATIC CYTOCHROME P-450 ACTIVITIES FOLLOWING INHALATION EXPOSURE TO p-CHLOROBENZOTRIFLUORIDE

Abstract

p-Chlorobenzotrifluoride (PCBTF), an intermediate in the synthesis of some herbicides, is currently being evaluated as an industrial solvent. The neurotoxicity of PCBTF was evaluated in a 90-day inhalation study in male and female Sprague-Dawley rats exposed for 6 h/day to target concentrations of 0, 10, 50, and 250 ppm PCBTF. Following exposure for 90 days, the livers were weighed, frozen, and microsomal fractions prepared to assess cytochrome P-450 (CYP450) content and activities. A significant increase in liver weight and CYP450 content in female rats was observed in the high exposure group (250 ppm), while the increase in males was not found to be statistically significant. 7-Ethyoxyresorufin O -deethylase (EROD), a measure of CYP1A1 activity, and acetanilide and phenacetin metabolism, a measure of CYP1A2 activity, were increased about twofold in both males and females at the high exposure level (250 ppm). Pentoxyresorufin O dealkylase (PROD) and benzyloxyresorufin O -dealkylase (BROD), a measure of CYP2B activity, were increased approximately fivefold in males at 250 ppm; however, the increase in females at 250 ppm was only twofold. Relatively small changes were observed in chlorzoxazone hydroxylation (CYP2E1) in the male high exposure group, while there were no differences in the females. Conversely, nifedipine oxidation (CYP3A1/3A2) showed a small increase in the females at 250 ppm and no change in males. Western blots of protein levels correlated generally well with increases in enzyme activity (control vs. high exposure level) for CYP1A2, CYP2B, and CYP2E1. The relatively modest induction of a wide range of hepatic CYP450 activities was limited to rats exposed to the 250 ppm dose of PCBTF, supporting the NOEL of 50 ppm. In addition, the results suggest that there are gender differences associated with the induction of CYP450 activities.