Biomedical and Pharmaceutical Sciences
acute kidney injury; drug metabolism
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Approximately 2 million people worldwide and more than 670,000 Americans are affected by end-stage renal diseases (ESRD). The current standard of care for ESRD is kidney transplantation. However, the surgical procedure of kidney transplantation inherently involves ischemia, which interrupts blood flow and reduces oxygen, during kidney graft preservation. The ischemic period is followed by reperfusion (the restoration of blood flow to the transplanted graft), resulting in varying degrees of ischemia and reperfusion (I/R) injury. I/R injury is a leading cause of both organ dysfunction and graft failure. Furthermore, kidney I/R injury has been shown to cause remote organ damage, especially in the liver. The liver is the most important site of drug metabolism and clearance with cytochrome P450 enzymes (CYP450) as the largest family of drug metabolism enzymes. For this project, microsomal fractions, which contain CYP450 enzymes, were isolated from previously collected liver tissue from male rats subjected to bilateral kidney I/R injury. Animal groups include: control, sham, and I/R injury. Liver microsomes were incubated under physiological conditions with testosterone, a substrate for CYP2C11 and 3A isoforms. The formation of testosterone metabolites after a predetermined incubation period were analyzed using Ultra Performance Liquid Chromatography (UPLC). A comparison of the metabolites formed between control, sham, and I/R injury animals was used to explore the relationship between kidney I/R injury and CYP450 activity. Changes in CYP450 activity can alter liver metabolism and the clearance of drugs, leading to sub-therapeutic or toxic effects. Therefore, it is important to quantify any changes in CYP450 regulation in the liver following kidney I/R injury.