MUSK XYLENE INDUCES AND INHIBITS MOUSE HEPATIC CYTOCHROME-P-450 2B ENZYMES

The purpose of this work was to characterize the effects of musk xylen e 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%, c aused hepatocellular hypertrophy and increased total cytochrome P-450 a-fold over control. Microsomes from musk xylene-treated mice showed i ncreased activity for the dealkylation of ethoxy- and methoxyresorufin , results consistent with increased CYP1A1 and 1A2 protein levels dete rmined by Western blotting. No increase in pentoxyresorufin-O-dealkyla tion activity was seen, but musk xylene treatment markedly increased C YP2B protein levels. Preliminary in vitro studies showed that musk xyl ene inhibited mouse CYP2B enzymes (IC50 approximate to 1 mu M), but di d not affect the activities of CYP1A1 or 1A2. This inhibition was not NADPH-dependent. These results indicate that, in mice, musk xylene cau ses generalized hepatic changes similar to classical CYP2B inducers, H owever, musk xylene is also a potent inhibitor of the CYP2B enzymes. ( C) 1995 Academic Press, Inc.