Study on the development of the short-term screening model for chemical carcinogenic agents and its application in relation to biliary tract cancer.

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To develop a useful test for the short-term screening of carcinogenic agents in relation to biliary tract cancer we measured unscheduled DUA synthesis (UDS) in bovine bile duct epithelial cells in culture induced by MNNG, ENNG, MCA, DMN and AFB_1 which were used successfully in developing biliary tract neoplasms in experimental animals. MNNG and ENNG induced UDS without addition of S9. MCA elicited UDS only if S9 was added. Regardless of the presence or abscence of S9, DMN failed to induce UDS. DNA repair by AFB_1 was enhanced by the presence of S9. On the contrary in human gallbladder epithelial cells MCS and DMN induced UDS even in the abscence of S9 indicating the presence of activating system of MCS and DMN in human gallbladder epithelium. By applying more sensitive alkaline and neutral elution technique we successfully demonstrated DNA single-strand breaks by these agents in bovine bile duct epithelial cells. Thus alkaline and neutral elution/ primary biliary tract epithelial cell culture system provides an organ specific model than UDS for detecting genotoxicities of chemical agents to the biliary tract. Phospholipase A_2 and lysolecithin which are supposed to play a significant role in the carcinogenesis of the biliary tract in anomalous pancreatico-biliary duct union did not induce significant DNA strand breaks, which suggests neither of them is an initiator of the carcinogenesis by itself.