NOVEL INSIGHTS INTO PROTOPORPHYRIN IX-INDUCED LIVER INJURYSachar, Madhav (2016) NOVEL INSIGHTS INTO PROTOPORPHYRIN IX-INDUCED LIVER INJURY. Doctoral Dissertation, University of Pittsburgh. (Unpublished) This is the latest version of this item.
AbstractProtoporphyrin IX (PPIX) is an endogenous hepatotoxin produced by all the cells as an intermediate in the heme biosynthesis pathway. In normal conditions, PPIX is efficiently converted into heme. However, genetic disease or xenobiotics can disrupt homeostasis in the heme biosynthesis pathway to cause PPIX accumulation. The first part of my thesis research revealed the mechanism by which isoniazid dysregulates the heme biosynthesis pathway. Isoniazid is an anti-tuberculosis drug known to cause liver injury when used with rifampicin. Here, I showed that isoniazid treatment independently induced the accumulation of PPIX in the liver of wild-type mice. Isoniazid dysregulates the heme biosynthesis pathway in the liver in part through the induction of delta-aminolevulinate synthase 1 protein as well as by the downregulation of ferrochelatase protein. Results from this study established the porphyrinogenic properties of isoniazid and explained how isoniazid can potentiate toxicity when administered with rifampicin. In the second part of this thesis, I showed that the ATP-binding cassette sub family G member 2 (ABCG2) is a key facilitator in the PPIX-mediated liver injury. ABCG2 is an ATP dependent transporter present in the liver which excretes PPIX from hepatocytes into the bile. Using genetic and chemical PPIX-mediated liver injury mouse models, I showed that Abcg2 deficiency abolished liver injury. In the genetic mouse model, I showed that the deficiency of Abcg2 in bone marrow cells redistributed PPIX produced by bone marrow into the spleen and decreased PPIX available in the serum to be collected by the liver. Also, Abcg2-deficiency in hepatocytes reduced the excretion of PPIX into the bile duct thus preventing PPIX-induced bile-duct blockage and consequently averting colestatic liver injury. I further showed that accumulated PPIX in the hepatocytes with Abcg2 deficiency was metabolized into detoxified metabolite which was excreted easily into the bile for fecal elimination. This study is important as it provides a novel therapeutic approach for the management of PPIX-mediated liver injury. Collectively, this work has provided greater insights into drug-induced PPIX accumulation and mechanism of PPIX-mediated liver injury. In addition, it is hoped that this work can help to develop strategies for preventing PPIX-mediated liver injury. Share
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