Mitochondrial dysfunction and pathways of cell death in drug-induced liver injury [ 2002 - 2004 ]

Research Grant

Researchers: Dr Brett Jones (Principal investigator) ,  Prof Geoffrey Farrell

Brief description Drugs are an important cause of liver disease that can result in fatal liver damage or require liver transplantation. More than 500 drugs are reported to cause liver disease, but we know almost nothing about how drugs injure the liver. As well as prescribed drugs: panadol, either after self-poisoning or inadvertently taken in too high a dose in someone who is not eating or is taking other medications that interfere with panadol breakdown, is one of most common causes of acute liver failure. Further, several herbal medicines have been implicated as causing liver disease. This project is designed to help us understand why and how 3 particular drugs damage the liver. We will study panadol, diterpenoids the active ingredients of skullcap, a herbal medicine, and azathioprine (imuran), a drug commonly used to suppress rejection after kidney or liver transplantation which occasionally causes very severe liver disease. Our main hypothesis is that these drugs damage mitochondria, the energy generating structures that form the engine of all living cells. We already know a little about how drug metabolites of panadol and the diterpenoids can damage mitochondria, but no-one has proven that this is the most important way in which they damage the liver. For drugs like azathioprine in which liver damage is rare, we are proposing that genetic defects in the mitochondrial DNA are what could predispose to liver injury. Thus our measurements will include how much mitochondrial DNA damage is caused by the drugs. Panadol, diterpenoids and azathioprine cause liver cell death by differing pathways (called apoptosis and necrosis). There are plausible ways in which mitochondrial damage could start off either (or both) cell death pathways during drug-induced liver injury, and we plan to test these. The new knowledge gained about how drugs damage the liver will be instrumental in allowing us to design new approaches to treat this important problem.

Funding Amount $AUD 301,650.00

Funding Scheme NHMRC Project Grants

Notes Standard Project Grant