Musk xylene induces and inhibits mouse hepatic cytochrome P-450 2B enzymes.
The purpose of this work was to characterize the effects of musk xylene on mouse hepatic microsomal enzyme activities. Male B6C3F1 mice were dosed for 7 days at 0 or 200 mg musk xylene/kg after which microsomes were prepared. Musk xylene treatment increased liver weight by 40%, caused hepatocellular hypertrophy and increased total cytochrome P-450 2-fold over control. Microsomes from musk xylene-treated mice showed increased activity for the dealkylation of ethoxy- and methoxyresorufin, results consistent with increased CYP1A1 and 1A2 protein levels determined by Western blotting. No increase in pentoxyresorufin-O-dealkylation activity was seen, but musk xylene treatment markedly increased CYP2B protein levels. Preliminary in vitro studies showed that musk xylene inhibited mouse CYP2B enzymes (IC50 approximately 1 microM), but did not affect the activities of CYP1A1 or 1A2. This inhibition was not NADPH-dependent. These results indicate that, in mice, musk xylene causes generalized hepatic changes similar to classical CYP2B inducers. However, musk xylene is also a potent inhibitor of the CYP2B enzymes.
Lehman-McKeeman
L D
LD
Human Safety Department, Procter and Gamble Co., Cincinnati, OH.
Caudill
D
D
Young
J A
JA
Dierckman
T A
TA
D000818:Animals; D019388:Cytochrome P-450 CYP1A2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006984:Hypertrophy; D015151:Immunoblotting; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism; D014992:Xylenes / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D014992:Xylenes; C031447:musk xylene; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019388:Cytochrome P-450 CYP1A2