HEPATOCARCINOGENESIS (Z-NUMBER-2) MUTAGENESIS DURING INITIATION STAGE/

Previously, we developed a model for high incidence, endogenously gene rated hepatocellular carcinoma (HCC), the human alpha-1-antitrypsin (a lpha 1AT) Z gene transgenic mouse (Z#2). We now examine the potential utility of a model for endogenous carcinogenesis utilizing the Z#2 mou se also transgenic for the lacl gene, a convenient target for in vivo mutagenesis studies. We crossed the Z#2 line and mice transgenic for l ambda/lacl shuttle vector (Big Blue), for determination of lad mutant frequency during initiation of endogenous carcinogenesis. Five month o ld double transgenic mice (Z#2(+)/lacl(+)) successfully displayed: (1) the expected post-inflammatory stage of Z#2 carcinogenesis; and (2) h epatic lad mutants measured at frequencies (10(-5)-10(-4)) useful to m utagenesis studies. In this study, hepatic lad mutation frequencies in Z#2 transgenic mice appeared to be only slightly increased(< 2 X) whe n compared to age matched negative controls. In the future, it may be important to reconcile possibly limited lacl mutagenesis at the time o f initiation and demonstrated high incidence of hepatocarcinogenesis. (C) 1998 Elsevier Science B.V.