Cytochrome P450 enzymes (CYPs) play an important role in bioactivating or detoxifying polycyclic aromatic hydrocarbons (PAHs), common environmental contaminants. While it is widely accepted that exposure to PAHs induces CYPs, effectively increasing rates of xenobiotic metabolism, dose- and time-response patterns of CYP induction are not well-known. In order to better understand dose- and time-response relationships of individual CYPs following induction, we exposed B6129SF1/J mice to single or repeated doses (2–180 μmol/kg/d) of benzo­[a]­pyrene (BaP) or Supermix-10, a mixture of the top 10 most abundant PAHs found at the Portland Harbor Superfund Site. In hepatic microsomes from exposed mice, we measured amounts of active CYPs using activity-based protein profiling and total CYP expression using global proteomics. We observed rapid Cyp1a1 induction after 6 h at the lowest PAH exposures and broad induction of many CYPs after 3 daily PAH doses at 72 h following the first dose. Using samples displaying Cyp1a1 induction, we observed significantly higher metabolic affinity for BaP metabolism (K m reduced 3-fold), 3-fold higher intrinsic clearance, but no changes to the V max. Mice dosed with the highest PAH exposures exhibited 1.7–5-fold higher intrinsic clearance rates for BaP compared to controls and higher V max values indicating greater amounts of enzymes capable of metabolizing BaP. This study demonstrates exposure to PAHs found at superfund sites induces enzymes in dose- and time-dependent patterns in mice. Accounting for specific changes in enzyme profiles, relative rates of PAH bioactivation and detoxification, and resulting risk will help translate internal dosimetry of animal models to humans and improve risk assessments of PAHs at superfund sites.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants generated from combustion of carbon-based matter. Upon ingestion these molecules can be bioactivated by cytochrome P450 monooxygenases to oxidized toxic metabolites. Some of these metabolites are potent carcinogens that can form irreversible adducts with DNA and other biological macromolecules. Conjugative enzymes, such as glutathione S-transferases or UDPglucuronosyltransferases, are responsible for the detoxification and/or facilitate the elimination of these carcinogens. While responses to PAH exposures have been extensively studied for the bioactivating cytochrome P450 enzymes, much less is known regarding the response of glutathione S-transferases in mammalian systems. In this study, we investigated the expression and activity responses of murine hepatic glutathione S-transferases to benzo[a]pyrene exposure using global proteomics and activity-based protein profiling for chemoproteomics, respectively. Using this approach, we identified several enzymes exhibiting increased activity including GSTA2, M1, M2, M4, M6, and P1. The activity of one GST enzyme, GSTA4, was found to be downregulated with increasing B[a]P dose. Activity responses of several of these enzymes were identified as *

Objectives: To build a profile of the experiences of stroke in the oldest old in the Murrumbidgee region and compare variables with two younger cohorts to test hypotheses about background, treatment and outcomes. Methods: Prospective data from 100 stroke patients consecutively admitted to the Wagga Wagga Rural Referral Hospital Acute Stroke Unit was reviewed from a stroke database. Comparisons were made between the young old (65-74), old-old (75 to 84) and oldest old (85 and older). Results: Older stroke patients were predominantly female with poorer premorbid functional status. Atrial fibrillation (p = 0.008) and hypertension (p = 0.01) were more common with advancing age. Smoking rates (p = 0.006) were higher in younger patients. Stroke mechanism was predominantly cardioembolic in older patients. Outcomes were poorer with rates of dependency (p = 0.03) and residential aged care facility placement (p = 0.06) increased. Conclusion: These data signal how stroke may manifest in our ageing population in the future.