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DIETARY EXPOSURE OF PHENOBARBITAL TO MALE AND FEMALE CD1 MICE FOR 2 OR 7 DAYS: EXAMINATION OF IN-LIFE, HEPATOCELLULAR ENZYME, PROLIFERATION, AND GENE EXPRESSION RESPONSES.
Citation:
Kan, H. L., B. Gollupudi, A. Wood, J. Murray, S. Hester, A. Goetz, R. Currie, AND D. Geter. DIETARY EXPOSURE OF PHENOBARBITAL TO MALE AND FEMALE CD1 MICE FOR 2 OR 7 DAYS: EXAMINATION OF IN-LIFE, HEPATOCELLULAR ENZYME, PROLIFERATION, AND GENE EXPRESSION RESPONSES. Presented at Ssociety of Toxicology (SOT) Annual Meeting, Washington, DC, March 06 - 10, 2011.
Impact/Purpose:
These combined data will inform dose, time, and sex effects underlying PB hepatotoxicity
Description:
Phenobarbital (PB) is a barbiturate used to relieve anxiety and control epilepsy. PB is also an archetypical inducer of the constitutive androstane receptor (CAR), resulting in liver hypertrophy in humans and both liver hypertrophy and hyperplasia in rodents. In this study, male and female CD1 mice were exposed to dietary PB at 0, 0.15, 1.5, 15, 75, and 150 mkd for 2 or 7 days. Toxicokinetic investigations showed no deviation from linearity with male mice having a 1.5-fold higher plasma concentration then females. Male and female mice exposed to 150 mkd for 2 or 7 days had significantly increased liver weight associated with hepatocellular hypertrophy and increased mitotic figures. Liver quantitative PCR and enzyme activity (PROD and BROD) highlighted increased CAR activation at concentrations ≥15 mkd. Hepatocellular proliferation was increased at ≥15 mkd in males and ≥1.5 mkd in females at 7 days with females showing a 1.5-2 fold greater induction in proliferation compared to males at both time points. Global gene expression revealed little to no pathway alterations at doses ≥1.5 mkd and was sex>dose>time dependent. Cyp2blO was the strongest indicator of exposure with an overall response indicating increased cell proliferation and increased xenobiotic response consistent with apical measures. Similarly, multiple transcriptional pathways converging on increased cell proliferation were observed. Beyond a predominant metabolic transcriptional response affecting fatty acid and xenobiotic metabolism, some more subtle but significant signaling responses were observed; NRF2-mediated oxidative stress, inflammation, numerous cytokine, and apoptotic pathways. These combined data will inform dose, time, and sex effects underlying PB hepatotoxicity. This abstract does not reflect EPA policy.