Title

The Role of Cyclophilin D in Mitochondrial Mediated Drug Toxicity

Date of Completion

January 2011

Keywords

Health Sciences, Pharmacy

Degree

Ph.D.

Abstract

Drug-induced mitochondrial dysfunction has been implicated in many types of organ toxicity, including liver and intestine. The induction of the mitochondrial permeability transition (mPT) has been seen as a mechanism of this toxicity. The mitochondrial matrix protein cyclophilin D (CypD) is a key regulator of the mPT, lending itself as a potential target for therapeutic intervention. The overall aim of this research project is to explore the mPT as a potential mediator of drug-induced mitochondrial toxicity in intestine and liver. Small intestinal ulceration is a frequent and serious adverse effect associated with the use of non-steroidal anti-inflammatory drugs. Mitochondria have been implicated in ulcer development. We have shown that inhibition of the mPT pore by pharmacologic blockade of CypD resulted in significant protection from diclofenac injury in cultured enterocytes and a 70% reduction in intestinal ulcers in mice. Furthermore, Ppif-/- (the gene encoding CypD) mice show 80% ulcer reduction after diclofenac treatment compared to wild-type controls. These results demonstrate that CypD plays an integral role in small intestine ulceration and could potentially be a therapeutic target for cytoprotection. ^ Second, acetaminophen (APAP) is safe at therapeutic doses, but at overdose can cause severe hepatotoxicity. The mPT has been implicated in the pathogenesis of the disease; however the mechanisms of the pathogenesis of the disease remain unclear. CypD inhibition did not prevent liver toxicity in mice. However, we have shown that co-administration with the peroxynitrite decomposition catalyst FeTMPyP liver injury was partially protected, and mitochondrial 3-nitrotyrosine adduct levels were decreased. It was also shown that co-administation with the JNK inhibitor, SP600125 did attenuate toxicity only in wildtype mice. This could indicate that the JNK pathway is not critically involved in APAP toxicity in the absence of CypD. These results suggest that an overdose of APAP leads to hepatocellular injury through a peroxynitrite mediated, CypD independent, mode of cell death. ^