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 xylene (MX) and musk ketone (MK) treatment on rat hepatic cytochrome P450 enzymes. Male F344 rats were dosed orally with MX (10, 50 or 200 mg/kg) or MK (20, 100 or 200 mg/kg) for 7 days, after which CYP1A, 2B and 3A enzyme activities and protein levels were determined. MX treatment resulted in a two- to four-fold increase in the activity of CYP1A, 2B and 3A enzymes. For CYP1A and 3A, these changes were consistent with small increases in immunoreactive proteins. However, for CYP2B, despite only a three-fold increase in enzyme activity, protein levels were increased nearly 50-fold relative to control. This induction occurred by transcriptional activation of the CYP2B1 gene as evidenced by increased steady state CYP2B1 mRNA levels. In contrast to MX, MK treatment increased CYP2B activity, protein and mRNA levels. However MK treatment also increased CYP1A enzyme activity nearly 30-fold higher than control rats, a profile that was markedly different from MX, and very different from its effects in mice (Stuard, S.B., Caudill, D., Lehman-Mc-Keeman, L.D., 1997. Characterization of the effects of musk ketone on mouse cytochrome P450 enzymes. Fund. Appl. Toxicol. 40, 264-271). These results indicate 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.
Lehman-McKeeman
L D
LD
Human Safety Department, Procter and Gamble Co., Miami Valley Laboratories, Cincinnati, OH 45253-8707, USA. lehmannmckeemanld@pg.com
Caudill
D
D
Vassallo
J D
JD
Pearce
R E
RE
Madan
A
A
Parkinson
A
A
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D010476:Perfume / Q000633:toxicity*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D014992:Xylenes / Q000633:toxicity*
D010476:Perfume; D012333:RNA, Messenger; D014874:Water Pollutants, Chemical; D014992:Xylenes; C031447:musk xylene; C031448:musk ketone; D003577:Cytochrome P-450 Enzyme System