Different mechanisms of modulation of gap junction communication by non-genotoxic carcinogens in rat liver in vivo.
This is a comparative study of the mechanisms by which three different rodent non-genotoxic carcinogens modulate connexin-mediated gap junction intercellular communication in male rat liver in vivo. In the case of the peroxisome proliferating agent Wy-14,643, a non-hepatotoxic dose of 50mg/kg led to a marked loss of inter-hepatocyte dye transfer associated with a loss of both Cx32 and Cx26 protein expression. In contrast, p,p'-dichlorodiphenyltrichloroethane (DDT) at a non-hepatotoxic dose (25mg/kg) was not found to alter Cx32 or Cx26 expression or to produce a measurable Cx32 serine phosphorylation but did give a small, significant reduction of cell communication. Carbon tetrachloride (CCl(4)) did not affect cell communication (despite a small significant reduction of Cx32 content) at a non-hepatotoxic dose. Both loss of communication and Cx32 expression was observed only at a dose that caused hepatocyte toxicity as evidenced by increased serum alanine aminotransferase activity. Overall, the findings emphasise that loss of gap junctional communication in vivo can contribute to carcinogenesis by non-genotoxic carcinogens through different primary mechanism. In contrast to Wy-14,643 and DDT, the results with CCl(4) are consistent with a requirement for hepatotoxicity in its carcinogenic action.
Cowles
C
C
School of Biosciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Mally
A
A
Chipman
J K
JK
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D002273:Carcinogens / Q000737:chemistry / Q000633:toxicity*; D002450:Cell Communication / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D000072259:Connexin 26; D017630:Connexins / Q000378:metabolism; D003634:DDT / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D017629:Gap Junctions / Q000187:drug effects* / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015151:Immunoblotting; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D020675:Peroxisomes / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D000097002:Gap Junction beta-1 Protein
D000410:Alanine Transaminase; D002251:Carbon Tetrachloride; D002273:Carcinogens; D000072259:Connexin 26; D017630:Connexins; D003634:DDT; D010171:Palmitoyl Coenzyme A; D011743:Pyrimidines; D000097002:Gap Junction beta-1 Protein; C000607044:Gjb2 protein, rat; C006253:pirinixic acid