Effects of musk xylene and musk ketone on rat hepatic cytochrome P450 enzymes

The purpose of the present work was to characterize the effect of musk xyle ne (MX) and musk ketone (MK) treatment on rat hepatic cytochrome P450 enzym es, Male F344 rats were dosed orally with MX (10, 50 or 200 mg/kg) or Mf( ( 20, 100 or 200 mg/kg) for 7 days, after which CYP1A, 2B and 3A enzyme activ ities and protein levels were determined. MX treatment resulted in a two- t o four-fold increase in the activity of CYP1A, 2B and 3A enzymes. For CYP1A and 3A, these changes were consistent with small increases in immunoreacti ve proteins. However, for CYP2B, despite only a three-fold increase in enzy me activity, protein levels were increased nearly 50-fold relative to contr ol. This induction occurred by transcriptional activation of the CYP2B1 gen e as evidenced by increased steady state CYP2B1 mRNA levels. In contrast to MX, MK treatment increased CYP2B activity, protein and mRNA levels. Howeve r MK treatment also increased CYP1A enzyme activity nearly 30-fold higher t han control rats, a profile that was markedly different from MX, and very d ifferent from its effects in mice (Stuard, S.B., Caudill, D., Lehman-McKeem an, L.D., 1997. Characterization of the effects of musk ketone on mouse cyt ochrome P450 enzymes. Fund. Appl. Toxicol. 40, 264-271). These results indi cate that in rats, MX is an inducer of CYP2B enzymes, but these enzymes are not functionally active. In contrast, MK also induces CYP2B enzymes, with no concurrent inactivation. MK also exhibits a unique pattern of cytochrome P450 induction by increasing both CYP1A and CYP2B in rats. (C) 1999 Publis hed by Elsevier Science Ireland Ltd. All rights reserved.