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

Many nongenotoxic hepatocarcinogens can induce cell proliferation, and inhi bit apoptosis and gap-junctional-intercellular communication (GJIC). GJIC, the movement of small molecules (less than 1.2 kD) through membrane channel s, is important in regulating cellular homeostasis and differentiation. The inhibition of hepatic GJIC can increase cell proliferation and possibly, i nhibit apoptosis. In this study, the relationship between hepatic GJIC, pro liferation, and apoptosis was examined in rats treated for 7 days with tumo r-promoting doses of the nongenotoxic hepatocarcinogens phenobarbital(PB; 8 00 ppm), pregnenolone-16 alpha-carbonitrile (PCN; 1000 ppm), and Aroclor 12 54 (PCB; 100 ppm). In addition, 3-methylcholanthrene (3MC) was included as a negative control. PB, PCN, and PCB increased parenchymal-cell proliferati on and inhibited hepatic apoptosis, while no alteration in these growth par ameters was observed in 3MC-treated rats. GJIC, as measured by fluorescent- dye transfer through intact liver, was decreased neatly 50%, by PB, PCN, an d PCB, yet no effect on GJIC was observed in liver from 3MC-treated rats. T hese data indicate that compounds that inhibit GJIC in liver may be nongeno toxic hepatocarcinogens, which occurs simultaneously during increased cell proliferation and inhibited apoptosis. (C) 2000 Elsevier Science Ireland Lt d. All rights reserved.