Treatment of B6C3F1 mice with acenaphthylene, acenaphthene,fluorene, phenanthrene, anthracene and dibenzofuran resulted in induction of hepatic microsomal methoxyresorufln O-deethylase (MROD) activity. Acenaphthylene was the most potent inducer of MROD, a Cypla2-dependent activity, and was utilized as a prototypical inducer for this group of tricyclic hydrocarbons. Acenaphthylene (300mg/kg) caused a < 80-fold induction of hepatic microsomal MROD activity; no induction was observed in kidney or lung. Analysis of induced hepatic microsomes with antibodies to Cyplal and Cypla2 showed that acenaphthylene induced immunoreactive Cypla2 but not Cyplal proteins and subsequent mRNA analysis confirmed with a cDNA probe for Cyplal and Cypla2 that acenaphthylene induced Cypla2 but not Cyplal mRNA. Results from nuclear run-on experiments using hepatic nuclei showed that acenaphthylene caused an ∼4-fold increase in the rate of Cypla2 gene transcription in B6C3F1 mice. Results of competitive binding studies indicated that the tricyclic hydrocarbons did not competitively displace [3H]2r3,7,8-tetrachlorodibenzo-p-dioxin or [3H]benzo[a]pyrene from the mouse hepatic cytosolic aryl hydrocarbon (Ah) receptor or 4S carcinogen binding protein respectively. The data indicate that acenaphthylene and related tricyclic hydrocarbons induce Cypla2 gene expression in B6C3F1 mice via an Ah receptor-independent pathway. Thus, tricyclic hydrocarbons induce Cypla2 without the co-induction of Cyplal and therefore these relatively non-toxic compounds can be used to further probe the role of Cypla2 in the metabolism and metabolic activation of diverse chemical carcinogens.
ASJC Scopus subject areas
- Cancer Research