Inhibition of gap-junctional-intercellular communication in intact rat liver by nongenotoxic hepatocarcinogens

• Published in: Toxicology (Amsterdam) 2000-04, Vol.146 (1), p.15-22
• Main Authors: Kolaja, Kyle L, Engelken, Dustin T, Klaassen, Curtis D
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - toxicity; Cell communication; Cell Communication - drug effects; Cell Division - drug effects; Chemical agents; Chlorodiphenyl (54% Chlorine) - toxicity; Dextrans - chemistry; Fluorescent Dyes - chemistry; Gap junctions; Gap Junctions - drug effects; Image Processing, Computer-Assisted; Immunohistochemistry; Isoquinolines - chemistry; Liver; Liver - drug effects; Male; Medical sciences; Methylcholanthrene - toxicity; Microscopy, Fluorescence; Nongenotoxic hepatocarcinogens; Phenobarbital - toxicity; Pregnenolone Carbonitrile - toxicity; Proliferating Cell Nuclear Antigen - analysis; Random Allocation; Rats; Rats, Sprague-Dawley; Rhodamines - chemistry; Signal Transduction - drug effects; Specific Pathogen-Free Organisms; Tumors
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/S0300-483X(00)00162-1

Many nongenotoxic hepatocarcinogens can induce cell proliferation, and inhibit apoptosis and gap-junctional-intercellular communication (GJIC). GJIC, the movement of small molecules (less than 1.2 kD) through membrane channels, is important in regulating cellular homeostasis and differentiation. The inhibition of hepatic GJIC can increase cell proliferation and possibly, inhibit apoptosis. In this study, the relationship between hepatic GJIC, proliferation, and apoptosis was examined in rats treated for 7 days with tumor-promoting doses of the nongenotoxic hepatocarcinogens phenobarbital (PB; 800 ppm), pregnenolone-16α-carbonitrile (PCN; 1000 ppm), and Aroclor 1254 (PCB; 100 ppm). In addition, 3-methylcholanthrene (3MC) was included as a negative control. PB, PCN, and PCB increased parenchymal-cell proliferation and inhibited hepatic apoptosis, while no alteration in these growth parameters was observed in 3MC-treated rats. GJIC, as measured by fluorescent-dye transfer through intact liver, was decreased nearly 50% by PB, PCN, and PCB, yet no effect on GJIC was observed in liver from 3MC-treated rats. These data indicate that compounds that inhibit GJIC in liver may be nongenotoxic hepatocarcinogens, which occurs simultaneously during increased cell proliferation and inhibited apoptosis.