Effect of 3'-methoxy-4'-nitroflavone on benzo[a]pyrene toxicity. Aryl hydrocarbon receptor-dependent and -independent mechanisms.
This laboratory has studied a number of flavone derivatives for aryl hydrocarbon receptor (AhR) agonist and antagonist potential using cell-free and cell culture systems. The current report extends these investigations by testing the potent AhR antagonist 3'-methoxy-4'-nitroflavone (3'M4'NF) for in vivo activity. Wild-type C57Bl/6 male mice were treated with solvent, benzo[a]pyrene (B[a]P; 150 mg/kg), or concurrently with B[a]P and 3'M4'NF (60 mg/kg; delivered as a split dose). Since B[a]P is bioactivated to genotoxic metabolites by AhR-regulated enzymes, we measured B[a]P-induced chromosomal damage in peripheral blood (i.e. micronuclei) to characterize the antagonistic potential of 3'M4'NF in vivo. The influence of AhR signal transduction was investigated further by challenging wild-type and Ahr null allele mice with B[a]P with and without a 3'M4'NF co-treatment. The micronucleus data obtained from these experiments indicated that 3'M4'NF can attenuate the genotoxicity of B[a]P significantly. Since 3'M4'NF also protected Ahr null allele mice from B[a]P-induced genetic damage, it was apparent that AhR-independent mechanisms contribute to the effects observed. However, as opposed to the protective effects observed with the micronucleus endpoint, histological observations and lethality data indicated that some B[a]P effects are enhanced by 3'M4'NF. Potentiated B[a]P toxicity may be explained by inhibition of basal and induced CYP1A1/2 activities. Both in vitro and in vivo data presented herein support this hypothesis.
Dertinger
S D
SD
Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
Lantum
H B
HB
Silverstone
A E
AE
Gasiewicz
T A
TA
D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology; D001564:Benzo(a)pyrene / Q000037:antagonists & inhibitors* / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004347:Drug Interactions; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors* / Q000378:metabolism
C091768:3'-methoxy-4'-nitroflavone; D016587:Antimutagenic Agents; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D005419:Flavonoids; D009153:Mutagens; D018336:Receptors, Aryl Hydrocarbon; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2