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Our Research Group:

Chief Investigator:
A/Prof Philip Burcham BSc(Hons) PhD
School of Medicine & Pharmacology, The University of WAThis laboratory was established at UWA in mid-2005 following relocation of the Chief Investigator from the University of Adelaide. Openings for Honours and postgraduate students are presently available in the laboratory.
Please contact Dr Burcham for further details.

Our Research Interests:
Life in the modern world poses many potential risks since we all are exposed to synthetic chemicals in the workplace, around the home and garden, or during leisure and recreational activities. Moreover, there is growing realisation that endogenous substances – chemicals produced during normal cellular metabolism –also damage vital cell components such as DNA and proteins. Such damage plays a central role in the ageing process. Work within our laboratory focuses on clarifying chemical and biochemical pathways of cell damage by toxic chemicals of both foreign and endogenous origin. Also, we are very interested in identifying new drug strategies for protecting cells against harmful chemicals.

Ablating the Toxicity of Acrolein With Nucleophilic Drugs

Although it comprises just a handful of carbon, oxygen and hydrogen atoms, acrolein is a highly reactive and toxic chemical that causes severe health problems in exposed individuals. It is formed during the metabolism of certain anticancer drugs such as cyclophosphamide and is responsible for some of the serious side-effects in chemotherapy patients receiving such drugs. Acrolein also forms in large quantities during the combustion of organic matter and accordingly it is responsible for the much of the acute toxicity of inhaled smoke. Even more intriguingly, acrolein is produced during free radical-induced damage to fatty acids in cellular membranes. A growing body of data indicates acrolein produced within the body via membrane oxidation is important in a diverse range of human diseases including neurodegenerative conditions such as Alzheimer’s or Parkinson’s Diseases and even traumatic spinal cord injury.

Given acrolein’s role in these diverse diseases, our laboratory has developed an interest in blocking the toxicity of this noxious substance. We have found that the “old” blood-pressure lowering drug hydralazine has remarkable abilities to block acrolein toxicity, and are currently exploring the mechanisms underlying this phenomenon. This work is performed in collaboration with researchers at the University of Adelaide in South Australia.

DNA Damage by Carboxylic Acid Drugs

Following their ingestion into the body, many drugs undergo metabolism in the liver or gut wall to form inactive metabolites. One of the most important of these pathways of drug metabolism involves conjugation with an endogenous sugar in a reaction termed glucuronidation. Most of the time, glucuronide metabolites formed this way are chemically inert and so they are safely excreted from the body via the kidneys or bile. However, for certain drugs that contain carboxylic acid groups, the resultant glucuronides are chemically reactive and are able to trigger cell and tissue damage. While such damage is implicated in certain rare allergies that can occur with carboxylic acid-containing drugs, we have pioneered study of the ability of such glucuronide metabolites to damage the DNA of cells. This work is carried out in collaboration with Dr Betty Sallustio and co-workers at the Queen Elizabeth Hospital in Adelaide, South Australia.

Relevant Chief Investigator Publications

Burcham, P. C. (1999) Internal Hazards: Baseline DNA Damage by Endogenous Products of Normal Metabolism. Mutation Research, 443, 11-36.

Burcham, P.C., and Fontaine, F. (2001) Extensive protein carbonylation precedes acrolein-mediated cell death in mouse hepatocytes. J. Molecular & Biochemical Toxicology 15, 309-316.

Fontaine, F.R., Dunlop, R.A., Petersen, D.R., and Burcham, P.C. (2002) Oxidative bioactivation of crotyl alcohol to the toxic endogenous aldehyde crotonaldehyde: association of protein carbonylation with toxicity in isolated mouse hepatocytes. Chemical Research in Toxicology 15, 1051-1058.

Burcham, PC, Kaminskas, LM, Fontaine, FR, Petersen, DR, & Pyke, SM (2002) Aldehyde-sequestering drugs: tools for studying protein damage by lipid peroxidation products. Toxicology, 181-182C, 229-236.

Ghaoui, R., Sallustio, B.C., Burcham, PC and Fontaine, F.R. (2003) UDP-Glucuronosyltransferase-dependent bioactivation of clofibric acid to a DNA-damaging intermediate in mouse hepatocytes. Chemico-Biological Interactions 145, 201-211.

Burcham, P. C., Fontaine, F. R., Petersen, D. R., and Pyke, S. M. (2003) Reactivity with tris(hydroxymethyl)aminomethane confounds immunodetection of acrolein-adducted proteins. Chemical Research in Toxicology, 16, 1196-1201.

Burcham, P.C., Fontaine, F.R., Kaminskas, L.M., Petersen, D.R. and Pyke, S.M. (2004) Protein adduct-trapping by hydrazinophthalazine drugs: Role in cytoprotection against acrolein-mediated toxicity. Molecular Pharmacology, 65, 655-664.

Frank R. Fontaine, Yvette DeGraaf, Roula Ghaoui, Benedetta C. Sallustio, Edwards J., and Burcham, P. C. (2004). Optimisation of the comet genotoxicity assay in freshly isolated murine hepatocytes: detection of strong in vitro DNA-damaging properties for styrene. Toxicology In Vitro, 18, 343-350

Kaminskas, L. M., Pyke, S. M., and Burcham, P. C. (2004) Strong protein adduct-trapping accompanies abolition of acrolein-mediated hepatotoxicity by hydralazine in mice. Journal of Pharmacology & Experimental Therapeutics 310, 1003-1010.

Kaminskas, L. M., Pyke, S. M., and Burcham, P. C. (2004) Hydrazinophthalazine drugs efficiently trap the toxic short-chain 2-alkenals acrolein and crotonaldehyde. Organic & Biomolecular Chemistry, 2, 2578 - 2584