Nitroaromatic musks, including
musk ketone (MK; 2,6-dimethyl-3,5-dinitro-4-t-butylacetophenone), are chemicals used as
perfume ingredients in household products,
cosmetics, and toiletries.
Musk xylene (MX; 1,3,5-trinitro-2-t-butylxylene), another nitromusk, is not genotoxic but has been reported to produce mouse liver
tumors in a chronic bioassay. In addition, MX has been shown to both induce and inhibit mouse liver
cytochrome P450 2B (CYP2B)
isozymes. The ability of MX to inhibit CYP2B
enzyme activity is attributable to inactivation of the
enzyme by a specific
amine metabolite. MK is structurally similar to MX, but lacks the nitro substitution that is reduced to the inactivating
amine metabolite. Therefore, we hypothesized that MK would induce, but not inhibit, CYP2B
isozymes. To test this hypothesis, and to evaluate the effects of MK on mouse liver
cytochrome P450 enzymes, two sets of experiments were performed. To evaluate the ability of MK to induce
cytochromes P450, mice were dosed daily by oral gavage at dosages ranging from 5 to 500 mg/ kg MK for 7 days. This treatment resulted in a pleiotropic response in mouse liver, including increased liver weight, increased total microsomal
protein, and centrilobular hepatocellular
hypertrophy. At the highest dose tested, MK caused a 28-fold increase in CYP2B
enzyme activity and a small (approximately 2-fold) increase in both
cytochromes P450 1A and 3A (CYP1A and
CYP3A)
enzyme activities over control levels.
Protein and
mRNA analyses confirmed the relative levels of induction for CYP2B, CYP1A, and
CYP3A. In addition, the no-observable-effect level (NOEL) for CYP2B induction by MK was 20 mg/kg. To evaluate the ability of MK to inhibit
phenobarbital-induced CYP2B activity, mice were given 500 ppm
phenobarbital (PB) in the
drinking water for 5 days to induce CYP2B
isozymes, followed by a single equimolar (0.67 mmol/kg) oral gavage dose of either MK (198 mg/kg) or MX (200 mg/kg), and microsomes were prepared 18 h later. While MX inhibited more than 90% of the PB-induced CYP2B activity in the microsomes, MK caused only a small (about 20%) reduction in PB-induced CYP2B
enzyme activity. These results indicate that, like MX. MK is a PB-type inducer of mouse liver CYP2B
isozymes, but unlike MX, MK does not effectively inhibit PB-induced CYP2B
enzyme activity.