Effect of subchronic and chronic exposure to halogenated aromatic hydrocarbons on cytochrome P450 biomarkers in rats

Cytochrome P450s (CYPs) are a broad class of mixed-function-oxidase enzymes that are important in the metabolism of drugs, environmental chemicals, and endogenous hormones. Within the CYP1 family (including members CYP1A1, 1A2, 1B1), gene induction is mediated through binding of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) and other dioxin-like halogenated aromatic hydrocarbons (HAHs) to the aryl hydrocarbon receptor (AhR). The impact of these environmental contaminants is very important since they can modulate CYP1 enzymes responsible for the metabolism and activation of procarcinogens into reactive species that are capable of causing cancer. Current research suggests that metabolism of estradiol (E₂) may be a preliminary step in tumor initiation.; The purposes of this dissertation was to assess the dose related modulation of dioxin-responsive CYP1 enzymes and 17β-estradiol metabolism in rat liver and lung tissues and determine the association of these biomarker effects with the carcinogenic potency of TCDD and related HAHs. This dissertation utilized banked frozen liver and lung tissues from female Sprague-Dawley rats that were part of the National Toxicology Program (NTP) sponsored cancer bioassay of TCDD and related HAHs conducted by Battelle (Columbus, Ohio). Rats were exposed daily by oral gavage to TCDD, and three other HAHs, individually and in defined mixtures.; The results from these studies demonstrate that microsomes from rat liver and lung effectively metabolize estradiol into both 2-hydroxyestradiol (2-OHE ₂) and 4-hydroxyestradiol (4-OHE₂), a known animal carcinogen and speculated human carcinogen. In addition, microsomes from HAH treated animals showed elevated estradiol metabolism and this increase was associated with an enhancement in both CYP1B1 protein and mRNA. Liver samples were found to produce more 4-hydroxyestradiol compared to lung. In addition to serving as a sensitive biomarker of exposure to TCDD and related HAHs, the CYP biomarker data from this dissertation will be compared to the tissue-specific cancer and chemical dosimetry data from these animals that are currently being obtained by the NTP study. Together, these results will be able to establish whether one or more of these CYP activities is a biomarker for the carcinogenic activity of TCDD and related HAHs.