DNA, PROTEINS & CARBON TETRACHLORIDE HEPATOTOXICITY

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The long term objective of the project are to gain knowledge baout how free radical causing chemicals later genetic material and/or its expression, by studying the effects of the hepatotoxin CC14 on liver DNA and different nuclear (n) proteins. The observed effects would be correlated with the already known markedly different response of livers from different animal species or strains to CC14 action (necrosis, cirrhosis, cancer) (from now on in text referred as the "liver response to CC14"). The present project specific aims are: a) To verify whether there is a correlation between the covalent binding (CB) of 14CC14 to DNA or to different n-protein fractions and the known "liver response to CC14" of different animal species or strains. a) To initiate structural studies of the adducts formed when the CC13 free radicals react with DNA bases and amino acids. c) To verify whether there is a correlation between CC1 ability to promote lipid peroxidation (LP) "in vivo" or "in vitro" (liver slices, micorsomes and nuclei) and the known "liver response to CC14" of different animal species or strains. d) To verify whether arachidonic acid degradation products produced during LP (e.g., 4 hydroxynonenal) are able to CB "in vivo" or "in vitro" to DNA or n- proteins. e) To study CC13 induced alterations in DNA bases and amino acids not attributable to either CB or LP (e.g., cross links formation, breakdown). To achieve these goals we plan: a) To islate highly purified DNA and different n-protein fractions (e.g., histones, acidic, etc.) and to establish the extent of CB to them. b) To attempt identification of altered bases or nucleosides and amino acids by HPLC (UV/14C/fluoroscence.electrometric detection) and/or by GLC/MS under different experimental conditions. e) To establish whether CC14 promotes nuclear LP as determined by ethanepenthane or malondialdehyde or 4 hydroxynonenal production. Major Health Implications of The Project: To achieve a better understanding of free radical induced alterations in DNA and n-proteins and their potential role in acute and long term chemically n=induced liver damage. Results might give an insight to mechanisms of action of liver carcinogens of weak or null mutagenic nature as is CC14.