This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This proposal seeks to determine the effect of short-term administration of DCA on the expression of maleylacetoacetate isomerase/glutathione S-transferase zeta (MAAI/GSTz) in human liver and to correlate this effect with plasma concentrations of DCA and urinary excretion of tyrosine catabolites. The rationale for this study is predicated on the fact that DCA is biotransformed to glyoxylate by MAAI, which also is the penultimate enzyme in the breakdown of tyrosine and phenylalanine. We believe the enzyme is highly susceptible to inhibition by DCA, since even environmental doses of the compound alter its expression in the livers of rats and delay its own plasma kinetics. However, proof of the effect of DCA on the human enzyme has not previously been obtained. We will recruit adults who are scheduled to undergo elective liver surgery for benign liver disease or other operative procedures for benign conditions in which wedge resection of the liver poses minimal additional risk. We hypothesize that DCA exhibits a dose-dependent inhibition of the expression of human liver MAAI and that this effect can be correlated with both plasma DCA concentrations and urinary excretion of key tyrosine metabolites.
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