Low-level m-Xylene inhalation alters pulmonary and hepatic cytochrome P-450 activity in the rat.
m-Xylene is a commonly used industrial solvent that has been shown to alter mixed-function oxidase (MFO) activity, in an organ- and isozyme-specific pattern, following intraperitoneal administration of the solvent. The purpose of this work was to determine whether similar alterations occurred in cytochromes P-450 (CYP) following m-xylene inhalation, the primary route of occupational exposure. A single 6-h exposure to m-xylene resulted in the inhibition of aryl hydrocarbon hydroxylase (AHH) activity in the lung while the activity of AHH was unchanged in the liver. CYP 2B1 activity, which is responsible for the metabolism of benzo[a]pyrene (BaP) to relatively nontoxic metabolites, was decreased in lung but not in liver. The activity of CYP 1A1, responsible for the metabolism of BaP to reactive/toxic products, was not altered in lung or liver. The CYP 2B1/1A1 ratio is an indirect indicator of the pattern of BaP toxication/detoxication. This ratio was decreased in lung, suggesting that BaP metabolism is shifted toward toxication. CYP 1A2 and CYP 4B1 activity was decreased in the lung while remaining unchanged in the liver. CYP 2E1 activity was also inhibited in lung while its activity was increased in the liver. This organ-specific inhibition of pulmonary cytochromes P-450 may be due to the lower MFO activity in the lung compared to liver. Alteration of the cytochromes P450 by m-xylene could result in a change in the metabolic profiles of xenobiotics in coexposure or subsequent exposure scenarios in increased or decreased toxicity in an organ-specific fashion.
Foy
J W
JW
Toxicology Program, Northeastern University, Boston, Massachusetts, USA.
Silverman
D M
DM
Schatz
R A
RA
D000280:Administration, Inhalation; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents; D014992:Xylenes / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*
D007527:Isoenzymes; D012997:Solvents; D014992:Xylenes; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C031285:3-xylene