Drug toxicity is the number one cause of acute liver failure, and hepatotoxicity is the most common reason why drugs are withdrawn from the US market or are stopped from clinical development. Interestingly, studies in rodents show that the liver acquires resistance to chemical injury following sub-lethal administration of hepatotoxicants such as acetaminophen (APAP) and carbon tetrachloride (CCl4). Similar tolerance is seen in a subset of human patients that use APAP. Currently, the mechanism of this resiliency is not known. It likely involves compensatory changes in response to oxidative and inflammatory signals triggered by hepatotoxicant exposure. A better understanding of this phenomenon is important since it may represent a source of clinically relevant drug-disease interactions in individuals with acute liver injury. Changes in transport protein-mediated influx and efflux of xenobiotics could contribute to hepatotoxicant resistance. Preliminary data from this laboratory show significant changes in gene and protein expression for a number of multidrug resistance proteins (Mrps) in mice receiving APAP and CCI4 treatment. We hypothesized that changes in expression of Mrp transporters during chemical-induced liver injury is a compensatory mechanism by which hepatocytes acquire resistance to subsequent hepatotoxicant challenge. We propose to test this hypothesis by first, investigating the temporal and zonal changes in expression and localization of hepatic Mrps following APAP and CCI4 treatment. Then, we will determine if inflammatory mediators contribute to this response by modulating cellular sources of cytokines. The final experiments will examine the role of the transcription factor-E2 p45-related factor 2 (Nrf2) in regulating transporter gene expression in mice lacking Nrf2 during injury and recovery from APAP and CC4 treatment. Nrf2 coordinately regulates the expression of drug metabolizing and detoxification genes. Its role in regulating Mrps has not been investigated. The proposed studies are expected to demonstrate that changes in liver transport protein expression following hepatotoxicant exposure represent an adaptation process that prevents accumulation of certain chemicals. This adaptive response may be essential for hepatocyte survival during periods of injury and regeneration. A comprehensive characterization of transport protein expression under the experimental conditions described in the proposal is of great relevance to human health. This information should give us an indication of the potential susceptibility of individuals with acute liver injury to pharmaceuticals that: a.) require transporter function for their excretion from the liver, and/or b). generate mediators of inflammation and injury that can be eliminated via transporter action.
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