INHIBITION OF RAT LUNG MIXED-FUNCTION OXIDASE ACTIVITY FOLLOWING REPEATED LOW-LEVEL TOLUENE INHALATION - POSSIBLE ROLE OF TOLUENE METABOLITES

Toluene is a commonly used solvent that has been shown to alter mixed- function oxidase (MFO) activity, in an organ- and isozyme-specific pat tern, following intraperitoneal administration. The purpose of this st udy was to determine whether similar changes occurred following repeat ed, low-level inhalation exposure, and to investigate the role of tolu ene metabolites in these alterations. Exposure to 375 ppm toluene, 6 h /d for up to 5 d, resulted in significant inhibition of the activity o f pulmonary arylhydrocarbon hydroxylase (AHH), cytochrome P-4502B1 (CY P2B1), and CYP4B1, but not CYP1A1. After exposure to lower toluene lev els (125 ppm, 6 h/d, 3 d), the activities of lung AHH, CYP2B1, and CYP 4B1 were also significantly decreased, but in a dose-related manner. M FO activity was not consistently altered in liver. Control pulmonary o r liver microsomes were incubated with various concentrations (0.01-10 mM) of toluene or its metabolites and CYP2B1, CYP1A1, and/or CYP4B1 a ctivities were subsequently determined. Benzaldehyde produced a signif icant dose-related inhibition in the activity of all three lung P-450s examined (IC50 10(-3) M). Toluene was found to be a more potent inhib itor of lung CYP2B1 and CYP1A1 (IC50, 10(-4) M) than benzaldehyde, but neither toluene nor benzyl alcohol was an effective inhibitor of lung CYP4B1. Toluene and its metabolites were weaker inhibitors of CYP1A1 than of CYP2B1. For CYP2B1 and CYP1A1, the order of inhibitory potency was toluene > benzaldehyde > benzyl alcohol and suggests that both th e parent molecule and its metabolites may act in concert to inhibit ca talytic activity of these cytochromes. The MFO inhibition seen after r epeated low-level tolune inhalation exposure could result in altered m etabolic profiles of other xenobiotics in an organ-specific fashion.