Pharmacogenetic Analysis in Mice (II)

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The lack of knowledge about the genetic variables that could be used for medication and dosage selection represents a major barrier to the clinical utilization of pharmacogenomic information. To enable the routine use of pharmacogenomic testing in clinical practice, efficient strategies for identifying the genetic variables that affect drug metabolism, mechanism of action ortoxicity must be developed and utilized. We will further develop an experimental system that will enable the factors affecting the metabolism of commonly used medications to be efficiently and rapidly identified in mice. An in vitro system that enables distinct steps (phase 1,11 and III) in drug disposition to be efficiently analyzed in vitro will be established. Strain-specific pharmcokinetic pharmacodynamic response data will evaluated using a haplotype-based computational method to identify genetic loci responsible for variation in response to the drugs. As a demonstration of utility of computational genetic analysis for understanding drug toxicty, we will identify the genetic factors contributing to resistance to acetaminophen-induced liver toxicity. This is a very important problem for human health. Acetaminophen toxicity has become the number one cause of acute liver failure in this country; 42% of acute liver failure cases treated in tertiary medical centers result from acetaminophen toxicity. The following specific goals will be completed: 1) To enable computational pharmacogenetic analysis, polymorphisms in over 500 murine genes that are responsible for phase I, II and III drug biotransformation will be identified and alleles characterized across 20 inbred mouse strains. 2) To enable rapid identification of the enzymes mediating phase I and II biotransformation reactions for prescribed medications, an in vitro pharmacogenetic analysis system will be developed. The metabolites produced after in vitro incubation of drugs in a microtiter plate format with liver extracts prepared from 15 inbred strains will be quantitatively characterized, and then analyzed by computational haplotype-based genetic mapping. 3) To demonstrate that computational pharmacogenetics can also identify mechanisms mediating drug-induced toxicity, the genetic basis for resistance to acetaminophen-induced liver toxicity in mice will be defined. 4) An in vitro pharmacogenetic analysis system will be developed that enables the identification of transporters mediating phase III biotransformation reactions.