title: Age-dependent carcinogenic susceptibility in rat liver is related to potential of gap junctional intercellular communication.
abstract: Connexin 32 (Cx32) is a major gap junction protein in the liver. The authors previously demonstrated that transgenic rats carrying a dominant negative mutant of Cx32 (Cx32ΔTg) have much decreased capacity for gap junctional intercellular communication (GJIC) and increased susceptibility to diethylnitrosamine (DEN)-induced hepatocarcinogenesis as compared to littermate wild-type (wt) rats. To evaluate the age-dependent susceptibility to DEN-induced hepatocarcinogenesis and alteration of GJIC function, male Cx32ΔTg and wt rats at 10, 30, or 85 weeks old were given a single intraperitoneal administration of DEN (40 mg/rat) and sacrificed 12 weeks later. The number and area of glutathione S-transferase placental form (GST-P)-positive preneoplastic foci were significantly increased in the liver of 10- and 30-wk-old Cx32ΔTg rats compared with age-matched wt. However, in the 85-wk-old rats, both Cx32ΔTg and wt rats had similarly large number and area of GST-P-positive foci, and the difference was not significant. Interestingly, function of hepatic GJIC was reduced and protein and mRNA expression of Cx32 were decreased with aging in wt rats. These results suggest that a decline of hepatic intercellular communication through gap junction results in increased susceptibility to DEN-induced hepatocarcinogenesis in aged rats.
authors.affiliation: Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan. ayaito@med.nagoya-cu.ac.jp
authors.forename: Aya
authors.initials: A
authors.lastname: Naiki-Ito
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kato
authors.forename: Makoto
authors.initials: M
authors.lastname: Asamoto
authors.forename: Taku
authors.initials: T
authors.lastname: Naiki
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Shirai
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects*; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D004052:Diethylnitrosamine / Q000494:pharmacology; D004198:Disease Susceptibility / Q000378:metabolism*; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D000097002:Gap Junction beta-1 Protein
chemical_list: D002273:Carcinogens; D017630:Connexins; D004052:Diethylnitrosamine; D005982:Glutathione Transferase; D000097002:Gap Junction beta-1 Protein