Metabolic flux profiling of reaction modules in liver drug transformation

With appropriate models, the metabolic profile of a biological system may be interrogated to obtain both significant discriminatory markers as well as mechanistic insight into the observed phenotype. One promising application is the analysis of drug toxicity, where a single chemical triggers multiple responses across cellular metabolism. Here, we describe a modeling framework whereby metabolite measurements are used to investigate the interactions between specialized cell functions through a metabolic reaction network. As a model system, we studied the hepatic transformation of troglitazone (TGZ), an antidiabetic drug withdrawn due to idiosyncratic hepatotoxicity. Results point to a well-defined TGZ transformation module that connects to other major pathways in the hepatocyte via amino acids and their derivatives. The quantitative significance of these connections depended on the nutritional state and the availability of the sulfur containing amino acids.