Effect of low-level short-term o-xylene inhalation of 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 intraperitoneal (ip) administration. Similar MFO alterations have been observed after ip or inhalation exposure to other methyl benzenes. These MFO alterations shifted the metabolism of the carcinogen benzo[a]pyrene (BaP) toward formation of toxication metabolites in lung. The purpose of this study was to determine whether o-xylene inhalation caused similar MFO changes and whether these alterations were reflected in altered BaP metabolism and BaP-DNA adduct formation. o-Xylene (300 ppm, 6 h) decreased the activity of arylhydrocarbon hydroxylase (AHH) in lung. CYP2B1 activity (benzyloxyresorufin O-dealkylase; BROD), which is responsible for metabolism of BaP to relatively nontoxic metabolites, was decreased in lung, as was, to a lesser extent, CYP1A1 (ethoxyresorufin O-dealkylase; EROD), which is responsible for metabolism of BaP to reactive/toxic metabolites. The BROD/EROD ratio, an indirect indicator of the pattern of BaP toxication/detoxication, was decreased in lung, suggesting that BaP metabolism is shifted toward toxication. No MFO alterations 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 decreased. In liver, o-xylene increased 9-OH BaP formation, while 4,5- and 9,10-diols as well as total diols were decreased. The toxication/detoxication ratios for BaP individual and total metabolite groups were increased in lung microsomes and unaltered in liver. The major BaP-DNA adduct, BaP diol epoxide-N2-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 liver indicate that coexposure to organic solvents such as the methyl benzenes may alter the carcinogenesis of BaP, or other PAHs, in an organ-specific fashion.
Park
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Toxicology Program, Northeastern University, Boston, Massachusetts 02115, USA.
Schatz
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RA
D000280:Administration, Inhalation; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism*; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism*; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D051381:Rats; D014992:Xylenes / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*
D002273:Carcinogens; D018736:DNA Adducts; D014992:Xylenes; C056612:benzo(a)pyrene-DNA adduct; D001564:Benzo(a)pyrene; D006899:Mixed Function Oxygenases; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1