Effects of polychlorinated dibenzofurans on compounds in hepatic DNA of female Sprague-Dawley rats: Structure dependence and mechanistic considerations

Previous work indicated that covalent age-dependent DNA modifications of endogenous origin termed I-compounds may represent useful biomarkers for tumor promotion/carcinogenesis, as various tumor promoters/carcinogens, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and phenobarbital, reduce rat I-compound levels in liver, the target organ. The present study addressed the question as to whether polychlorinated dibenzofurans (PCDFs), which are related to TCDD and its congeners with regard to their toxic and biochemical properties, would also affect hepatic I-compound patterns and levels, and whether such effects would be chemical structure-dependent. Female Sprague-Dawley rats were treated once a week with a single dose (100 μg/kg) of 1,2,3,7,8-pentachlorodibenzofuran (1,2,3,7,8-PeCDF), 1,2,4,7,8-PeCDF, 2,3,4,7,8-PeCDF, or 2,3,4,6,7,8-hexachlorodibenzofuran (2,3,4,6,7,8-HeCDF) for 4 weeks and liver DNA was analyzed at the end of the last week by ³²P-postlabeling assay. No carcinogen-DNA adducts were detected; however, levels of both non-polar and polar I-compounds were reduced in a structure-dependent manner. Potencies increased in the order, control (100%, 122 modifications in 10⁹ DNA nucleotides = 1,2,4,7,8-PeCDF (104%) <1,2,3,7,8-PeCDF (80%) <2,3,4,7,8-PeCDF (61%) and 2,3,4,6,7,8-HeCDF (61%). Structure-activity relationships for total I-compounds, therefore, paralleled those reported for Ah receptor agonist activity, i.e., compounds that exhibit high cytosolic Ah receptor binding affinities and are also potent inducers of aryl hydrocarbon hydroxylase activity (1,2,3,7,8-PeCDF, 2,3,4,7,8-PeCDF, and 2,3,4,6,7,8-HeCDF) were active, while 1,2,4,7,8-PeCDF, which is a less potent Ah receptor agonist, was inactive. Polar I-compounds responded to a greater extent than did non-polar ones and, in general, individual I-compounds were affected differentially, thus decreased formation or increased removal of I-compounds played a role in the observed effects of the toxins on DNA. It is proposed that Ah receptor-mediated enzyme induction, particularly of cytochrome P450, is involved in reduced hepatic I-compound formation and that subnormal I-compound levels may contribute to tumor promotion.