Aryl hydrocarbon receptor signaling plays a significant role in mediating benzo[a]pyrene- and cigarette smoke condensate-induced cytogenetic damage in vivo

This laboratory has previously reported data suggesting that aryl hydrocarb on receptor (AhR) signaling may have a net potentiating effect on the DNA d amaging potential of cigarette smoke. The experiments described in this rep ort extend these studies by testing whether the potent AhR antagonist 3'-me thoxy-4'-nitroflavone (3'M4'NF) can modify the in vivo genetic toxicity of benzo[a]pyrene (B[a]P) and the complex mixture of chemicals in cigarette sm oke condensate (CSC), Initial experiments were designed to determine 3'M4'N F doses which can antagonize AhR in vivo but which have little effect on co nstitutive cytochrome P4501A (CYP1A) activity. These experiments took three forms: (i) zoxazolamine paralysis tests, a functional assay of cytochrome P450 CYP1A activity in 3'M4'NF-treated C57Bl/6J mice; (ii) co-treatment of Ahr null allele mice with 150 mg/kg B[a]P plus a range of 3'M4'NF concentra tions in order to evaluate the potential of the flavone to interact with no n-AhR targets which may affect B[a]P toxicity; (iii) an evaluation of the i n vivo AhR antagonist activity of 3'M4'NF using transgenic mice which carry a dioxin-responsive element-regulated lacZ reporter. Once an appropriate d ose range was determined, C57Bl/6J mice were challenged with B[a]P or CSC w ith and without 3'M4'NF co-treatment, Chromosome damage was measured by sco ring the frequency of micronuclei in peripheral blood reticulocytes, Data p resented herein suggest that 3'M4'NF can protect mice from B[a]P-induced bo ne marrow cytotoxicity and genotoxicity, Furthermore, CSC-associated genoto xicity was abolished by the flavonoid, These data add support to our hypoth esis that AhR signaling has a net potentiating effect on the genetic toxici ty and, presumably, carcinogenicity of cigarette smoke.