| Liver damage as a result of exposure to prescription drugs is widely acknowledged as a serious human health problem, and there is a growing incidence of hepatotoxic reactions due to botanical supplements as their use has become more widespread. Many such reactions can be classified as "idiosyncratic". Inadequacies in clinical data from case reports and the shortage of experimental animal models hamper the understanding of idiosyncratic reactions. Unusual production of toxic drug metabolites, stimulation of specific immunity, and inflammatory stress are frequently quoted as causes, but most drugs lack definitive evidence supporting these mechanisms In this project, we give a brief overview of xenobiotic-induced liver toxicity under inflammatory conditions induced by bacterial lipopolysaccharide (LPS). Although ample experimental evidence suggests an impact of inflammation on the vulnerability of the liver to toxic effects of xenobiotics, a number of unanswered mechanistic questions remain. For example, the roles and sequence of oxidative stress, the coagulation system, and their interplay in this phenomenon has not been clearly established. In addition, whether analogous injury may occur in other organs has not been well studied. The role that inflammatory stress induced by exogenous inflammagens may play as a susceptibility factor is the subject of this dissertation project. We discuss the inflammatory stress hypothesis and use, as an example, monocrotaline (MCT), a pyrrolizidine alkaloid (PA) plant toxin that causes hepatotoxicity in humans and animals. The primary research goals of this project are to establish a mouse model to evaluate the inflammatory stress hypothesis, and to use it to understand the mechanisms of toxic responses in liver and kidney under these conditions. |
