Role of isozyme-specific inhibition of cytochrome P450IIB1 activity in m-xylene-induced alterations in rat pulmonary benzo(a)pyrene metabolism.
1. m-Xylene (1 g/kg, i.p., 1 h) increased formation of benzo(a)pyrene (BP) mutagenic bay region diols, BP-7,8-diol (66%) and BP-9,10-diol (56%) by rat pulmonary microsomal preparations, while formation of individual BP phenols and quinones was unaltered. 2. m-Xylene administration produced a decrease in cytochrome P450IIB1 activity as measured by pentoxy- and benzyloxy-resorufin O-dealkylation (PROD, BROD), while cytochrome P450IA1 activity, expressed as ethoxyresorufin O-dealkylation (EROD), was unaltered. 3. Pulmonary microsomal epoxide hydrolase activity was also unaltered by m-xylene. 4. In summary, m-xylene alters the relative contribution of P-450 isozymes to BP metabolism resulting in inhibition of BP detoxication and increased production of toxic metabolites.
Stickney
J A
JA
Toxicology Program, Northeastern University, Boston, MA 02115.
Silverman
D M
DM
Schatz
R A
RA
D000818:Animals; D001580:Benzopyrenes / Q000378:metabolism*; D019362:Cytochrome P-450 CYP2B1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008168:Lung / Q000201:enzymology*; D008297:Male; D008861:Microsomes / Q000201:enzymology*; D010088:Oxidoreductases / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014992:Xylenes / Q000494:pharmacology*
D001580:Benzopyrenes; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D014992:Xylenes; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019362:Cytochrome P-450 CYP2B1; D004851:Epoxide Hydrolases; C031285:3-xylene