Analysis of molecular mechanism of radiation-induced cancer and risk estimation

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To clarify the molecular mechanism of radiation-carcinogenesis, and apply it to the risk estimation, we conducted two experiments. Firstly, we analyzed the expression of genes in radiation-induced-mouse hepatomas. Mouse hepatomas were induced in B6C3F1 mice by 3Gy of ^<60>Coγ-ray exposure, and mRNAs were isolated from hepatomas and normal liver in the same mice. We identified differentially expressed genes by differential display technique. We found nineteen differentially expressed genes in hepatomas. Expressions of five genes were decreased and those of other fourteen genes were increase in hepatomas, including novel three genes named CRAD3 that was a member of cis-retinol/androgen dehydrogenase (CRAD) family, Sdf211 that was a member of Pmt/rt family, and A141-36 whose homology was not identified. CRAD plays an important role in androgen metabolism, which converts inactive 3α-adiol, into active dihydrotestosterone, (oxidative 3α-hydroxysteroid dehydrogenase activities : oxidative 3α … More -HSD activities) and consequently increases androgen activity. Actually, oxidative 3α-HSD activity in mouse hepatomas was found to be higher than that in normal liver at physiological 3α-adiol level. Dihydrotestosterone is well known to promote hepatocarcinogenesis. Therefore, the over-expression of CRAD3 must modify the radiation-induced mouse hepatocarcinogenesis by increasing local dihydrotestosterone level. Secondly, we try to clarify the involvement of spontaneous mutations in radiation carcinogenesis, because similarity of mutation spectra between radiation-induced and spontaneous cancers was well documented. We characterized mouse and human Revl gene which was a member of the UmuC/DinB/XPV gene family, played important roles in spontaneous mutations. Biochemical analysis of the mouse Rev1 protein revealed that the mouse Rev1 protein possessed a deoxycytidyl transferase activity as human REV1 protein. The expression of mouse Rev1 gene of primary embryonic fibroblasts in culture was induced by radiation exposure. This observation might be important, because the biochemical property suggested that the activity of the Rev1 protein was required for bypassing oxidative DNA damage by translesioh DNA synthesis during DNA replication. Less