Musk ketone enhances benzo(a)pyrene induced mutagenicity in human derived Hep G2 cells.
Musk ketone is a widely used artificial fragrance which has been identified in human fatty tissue and milk. The mutagenic and comutagenic effects of this compound were studied in micronucleus tests with a human derived hepatoma cell line (Hep G2). Exposure of the cells to MK alone in the range between 5 and 5000 ng/ml did not cause induction of MN. When the cells were treated simultaneously with MK (5-5000 ng/ml) and 0.2 microg/ml benzo(a)pyrene, no synergistic effects were detected; benzo(a)pyrene (B(a)P) itself caused an 1.5-fold increase of MN over the spontaneous background frequency (60 versus 39 MN/1000 binucleated cells). In a third experimental series, the cells were pretreated with MK for 28h and subsequently exposed to 0.2 microg/ml B(a)P. In this case, a pronounced comutagenic effect was observed: The LOAEL for MK was 0.05 microg/ml. With higher doses (0.5, 1.0 and 5.0 microg MK/ml), a significant increase of B(a)P induced MN frequencies was measured, the induction rates being 50, 66, and 88%, respectively. Additional measurements of 7-ethoxyresorufin deethylase indicated that MK induces cytochrome P450 isoenzymes (1A1) which play a key role in the activation of B(a)P. The results of the present study show that MK amplifies the genotoxic effects of B(a)P in human derived cells and indicate that exposure of humans to MK might increase their susceptibility to the health hazards of B(a)P and other polycyclic aromatic hydrocarbons.
Mersch-Sundermann
V
V
Department of Toxicology and Ecotoxicology, FB VI, University of Trier, 54286 Trier, Germany. mersch@rumms.uni-mannheim.de
Schneider
H
H
Freywald
C
C
Jenter
C
C
Parzefall
W
W
Knasmüller
S
S
D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004790:Enzyme Induction; D006801:Humans; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*; D010476:Perfume / Q000633:toxicity*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects; D014992:Xylenes / Q000633:toxicity*
D009153:Mutagens; D010476:Perfume; D014992:Xylenes; D001564:Benzo(a)pyrene; C031448:musk ketone; D019363:Cytochrome P-450 CYP1A1