Effect of low-level short-term o-xylene inhalation on benzo[a]pyrene (BaP)metabolism and BaP-DNA adduct formation in rat liver and lung microsomes

o-Xylene is a commonly used solvent that alters mixed-function oxidase (MFO ) activity in an organ- and isozyme-specific pattern following intraperiton eal tip) administration. Similar MFO alterations have been observed after i p or inhalation exposure to other methyl benzenes. These MFO alterations sh ifted the metabolism of the carcinogen benzo[a]pyrene (BaP) toward formatio n of toxication metabolites in lung. The purpose of this study was to deter mine whether o-xylene inhalation caused similar MFO changes and whether the se alterations were reflected in altered BaP metabolism and BaP-DNA adduct formation. o-Xylene (300 ppm; 6 h) decreased the activity of arylhydrocarbo n hydroxylase (AHH) in lung. CYP2B1 activity (benzyloxyresorufin O-dealkyla se; BROD), which is responsible for metabolism of BaP to relatively nontoxi c metabolites, was decreased in lung, as was, to a lesser extent, CYP1A1 (e thoxyresorufin O-dealkylase; EROD), which is responsible for metabolism of BaP to reactive/toxic metabolites. The BROD/EROD ratio, an indirect indicat or of the pattern of BaP toxication/detoxication, was decreased in lung, su ggesting that BaP metabolism is shifted toward toxication. No MFO alteratio ns were observed in liver. In lung microsomes, o-xylene increased formation of 7,8-BaP-diol, while 9,10-BaP-diol, 3-OH BaP, and 9-OH BaP were decrease d. In liver, o-xylene increased 9-OH BaP formation, while 4,5- and 9,10-dio ls as well as total diets were decreased. The toxication/detoxication ratio s for BaP individual and total metabolite groups were increased in lung mic rosomes and unaltered in liver. The major BaP-DNA adduct, BaP diet epoxide- N-2-deoxyguanosine, was increased in lung but decreased in liver microsomes from o-xylene-exposed rats. Four minor BaP-DNA adducts were formed in lung and three in liver, only one of which (liver adduct 3) was decreased. The o-xylene-induced increase in BaP adduct formation in lung and decrease in l iver indicate that coexposure to organic solvents such as the methyl benzen es may alter the carcinogenesis of BaP, or other PAHs, in an organ-specific fashion.