Date of Graduation
Agaricus bisporus mushrooms have been shown to be carcinogenic due to their arylhydrazine content, but the mechanism of the carcinogenesis has not been elucidated. Clues into the mechanism have been discovered in the metabolism of the arylhydrazines to arenediazonium ions and aryl radicals. Both of these compounds form DNA adducts, which may be relevant to carcinogenesis. Arenediazonium ions have been shown to activate signal transduction proteins associated with DNA damage and apoptosis. Previously, our group had shown that arenediazonium ions activate the apoptotic protein AP1. The activation of AP1 has been correlated to aryl radial generation, since the AP1 activation can be rescued with carbon radical scavengers but not oxygen radical scavengers. The studies reported herein takes the signal transduction pathways a step further and shows that arenediazonium ions activate the DNA damage signaling protein p53. This would imply that the aryl radicals are causing a significant amount of DNA damage, which cells attempt to repair. Since the aryl radicals are known to form C8-arylpurine DNA adducts, it will be important to study the affects of those DNA adducts specifically. The role of C8-arylpurine DNA adducts in the mechanism of arylhydrazine carcinogenesis has also been addressed in relation to DNA conformation and stability. Thermal denaturation, circular dichroism, and nuclear magnetic resonance were used to study modified oligonucleotides. The C8-arylpurine modified oligonucleotides exhibited distinct changes in conformation and duplex stability. The results from the study of DNA damage and C8-arylpurine DNA adduct affects indicate that C8-arylpurines are a major contributor in arylhydrazine carcinogenesis. Since aryl radials appear to cause the apoptotic and DNA damage responses, C8-arylpurines are implicated into the mechanism of carcinogenesis. Data showing that C8-arylpurines alter DNA conformation and duplex stability identifies that these DNA adducts will affect DNA-protein binding and DNA decomposition. Both effects could lead to an increase in DNA mutations, which may be the mechanism behind arylhydrazine carcinogenesis.
Daft, Jonathan R., "Arylhydrazine carcinogenesis and the synthesis of C8-arylpurine oligonucleotides: A study of DNA adduct effects on DNA conformation and stability." (2005). Graduate Theses, Dissertations, and Problem Reports. 8706.