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© 1984 Oxford University Press

research-article

Lack of Initiating or Promoting Activity of Six Benzodiazepine Tranquilizers in Rat Liver Limited Bioassays Monitored by Histopathology and Assay of Liver and Plasma Enzymes

B. REMANDET*, D. GOUY*, J. BERTHE*, G. MAZUE* and G. M. WILLIAMS{dagger}

*Centre de Recherches CLIN MIDY Sanefi Recherche, Montpellier, France {dagger}American Health Foundation Valhalla, New York 10595

Lack of Initiating or Promoting Activity of Six Benzodiazepine Tranquilizers in Rat Liver Limited Bioassays Monitored by Histopathology and Assay of Liver and Plasma Enzymes. RE-MANDET, B., GOUY, D., BERTHE, J., MAZUE, G., AND WILLIAMS, G. M. (1984). Fundam. Appl. Toxicol. 4, 152–163. Six benzodiazepine tranquilizers were tested in limited in vivo bioassays for their ability to initiate or promote the development of preneoplastic and neoplastic rat liver lesions. The benzodiazepines produced no liver altered hepatocellular foci during a 14-week period of administration whereas a large number were produced by the liver carcinogen, N-2-fluorenylacetamide. To assay for promoting activity and confirm the lack of initiating activity, N-2-fluorenylacetamide was used to produce altered foci and early neoplastic nodules in rat liver by 8 weeks of dietary administration and the benzodiazepines were then administered for 12 weeks. The liver neoplasm promoter phenobarbital had a substantial enhancing effect upon the persistence of early lesions but none of the benzodiazepines showed a similar effect. Thus in these limited bioassays monitored by histopathology, the benzodiazepine tranquilizers failed to exhibit either an initiating or a promoting action. In these studies, the liver and plasma enzymes, glutamate-pyruvate transaminase, glutamate-oxalacetic transaminase, lactic dehydrogenase, alkaline phosphatases, and {gamma}-glutamyltranspeptidase were monitored to determine if any alterations correlated with liver pathological changes. {gamma}-Glutamyltranspeptidase activity in both liver and plasma was markedly increased during initiation by N-2-fluorenylacetamide. Following cessation of carcinogen exposure, {gamma}-glutamyltranspeptidase remained elevated, providing an indication of past initiation. Administration of phenobarbital after N-2-fluorenylacetamide resulted in an elevation of liver and plasma {gamma}-glutamyltranspeptidase, but none of the benzodiazepines produced this effect and thus no biochemical evidence of a promoting effect on the liver was observed. Correlations between liver and plasma {gamma}-glutamyltranspeptidase and the occurrence of foci were excellent, indicating that determination of plasma activity can be used as an index of the process of hepatocarcinogenesis.


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