Effects of heptachlor epoxide on components of various signal transductionpathways important in tumor promotion in mouse hepatoma cells - Determination of the most sensitive tumor promoter related effect induced by heptachlor epoxide

The effects of the organochlorine (OC) liver tumor promoter heptachlor epox ide (HE; 0, 0.1, 1, 10, and 50 muM) on several cellular tumor promoter-sens itive parameters were studied in mouse 1c1c7 hepatoma cells in an effort to identify the most sensitive biomarker for OC promoter exposure and the cri tical pathway and target of OC promoters. The levels of Ca2+ in the endopla smic reticulum (ER) store, connexin43 (Cx43), PLC gamma (1), nPKC epsilon, and AP-I DNA binding in nucleus were studied to screen for effects induced by submicromolar HE levels. While all the parameters tested elicited effect s, particulate PLC gamma (1) and AP-1 DNA binding were found to be the most sensitive parameters affected by HE on both dose and temporal bases. Their levels were increased with 10- to 100-fold lower HE concentrations than we re required to affect nPKC epsilon or Cx43. Further, with the lower HE dosa ges, particulate PLC gamma (1) and nuclear AP-1 were positively modulated b y HE after 1 h versus 3 or 72 h for nPKC epsilon and Cx43. Ca2+ store deple tion was probably the third most sensitive parameter, after AP-1 and PLC ga mma (1). These results suggest the tyrosine kinase growth factor receptor p athway is the probable critical pathway for HE-induce tumor promotion with the critical target most likely being upstream of PLC gamma (1) and AP-1. T his work also demonstates that upon exposure to a tumor promoter such as HE , many hepatocellular effects or changes result, suggesting that a cellular -program shift occurs similar to that described by the resistant hepatocyte model after exposure to a carcinogen or enzyme inducer. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.