Aryl hydrocarbon (Ah) receptor-independent induction of Cyp1a2 gene expression by acenaphthylene and related compounds in B6C3F1 mice.
Treatment of B6C3F1 mice with acenaphthylene, acenaphthene, fluorene, phenanthrene, anthracene and dibenzofuran resulted in induction of hepatic microsomal methoxyresorufin O-deethylase (MROD) activity. Acenaphthylene was the most potent inducer of MROD, a Cyp1a2-dependent activity, and was utilized as a prototypical inducer for this group of tricyclic hydrocarbons. Acenaphthylene (300 mg/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 Cyp1a1 and Cyp1a2 showed that acenaphthylene induced immunoreactive Cyp1a2 but not Cyp1a1 proteins and subsequent mRNA analysis confirmed with a cDNA probe for Cyp1a1 and Cyp1a2 that acenaphthylene induced Cyp1a2 but not Cyp1a1 mRNA. Results from nuclear run-on experiments using hepatic nuclei showed that acenaphthylene caused an approximately 4-fold increase in the rate of Cyp1a2 gene transcription in B6C3F1 mice. Results of competitive binding studies indicated that the tricyclic hydrocarbons did not competitively displace [3H]2,3,7,8-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 Cyp1a2 gene expression in B6C3F1 mice via an Ah receptor-independent pathway. Thus, tricyclic hydrocarbons induce Cyp1a2 without the co-induction of Cyp1a1 and therefore these relatively non-toxic compounds can be used to further probe the role of Cyp1a2 in the metabolism and metabolic activation of diverse chemical carcinogens.
Chaloupka
K
K
Texas A&M University, College Station 77843-4466.
Santostefano
M
M
Goldfarb
I S
IS
Liu
G
G
Myers
M J
MJ
Tsyrolv
I B
IB
Gelboin
H V
HV
Krishnan
V
V
Safe
S
S
D000073:Acenaphthenes / Q000494:pharmacology*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology; D001572:Benzofurans / Q000494:pharmacology; D003433:Crosses, Genetic; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005449:Fluorenes / Q000494:pharmacology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010088:Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D010569:Perylene / Q000031:analogs & derivatives / Q000494:pharmacology; D010616:Phenanthrenes / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*
D000073:Acenaphthenes; D000873:Anthracenes; D000911:Antibodies, Monoclonal; D001572:Benzofurans; D005449:Fluorenes; D010616:Phenanthrenes; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C006706:benzoperylene; C042553:acenaphthylene; C041509:fluorene; C031181:phenanthrene; D010569:Perylene; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; C034020:anthracene; C042552:acenaphthene; C014211:2,3,7,8-tetrachlorodibenzofuran