The objective of this work is to determine the role of mitochondrial injury in cytotoxicity and in the multistep carcinogenesis induced by diverse polycyclic aromatic hydrocarbons, Aflatoxin B1 (AFB1), Benzo(Alpha)pyrene (BaP), and Dimethyl benzanthracene (DMBA) using various animal and cell models. Recent work in our laboratory has established that hepatic mitochondria contain inducible forms of cytochromes P-450 and epoxide hydrolase. Further, it has also been demonstrated that mitochondrial genetic and biosynthetic systems in mice and hamsters, which are resistant to aflatoxicosis, are heavily protected against the injurious effects of AFB1. Another key observation was that continued suppression of mitochondrial gene expression is associated with over expression of nuclear genes possibly due to disruption of communication between the two genetic systems. Based on this, we propose to carry out four major lines of experiments to determine the immediate and long-term effects of mitochondrial DNA injury to cellular processes and carcinogenesis. (1) The levels of mitochondrial cytochrome P-450 and epoxide hydrolase in cells and tissues known to be the targets for BaP and DMBA carcinogenesis and their correlation with the level of mitochondrial DNA modification. (2) A detailed analysis of mitochondrial DNA in tumor cells induced by structurally diverse polycyclic aromatic hydrocarbons like AFB1 and BaP to determine the precise nature of mutational events. (3) Qualitative and quantitative analysis of nuclear genetic information over expressed mitochondrial activity and its relationship to mitochondrial injury and mutations. (4) Use of liposome delivery system to study the state of mitochnodrial DNA and mitochondrial/nuclear interaction in cells and tissues resistant to AFB1 and DMBA carcinogenesis.
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