Heptachlor epoxide induces a non-capacitative type of Ca2+ entry and immediate early gene expression in mouse hepatoma cells.
The effects of the organochlorine (OC) liver tumor promoter heptachlor epoxide (HE) and a related non-tumor promoting OC, delta-hexachlorocyclohexane (delta-HCH), on the dynamics of intracellular calcium (Ca2+) were investigated in mouse 1c1c7 hepatoma cells. HE induced a non-capacitative, Ca2+ entry-like phenomenon, which was transient and concentration-dependent with 10 and 50 microM HE. The plasma membrane Ca2+ channel blocker SKF-96365 antagonized this HE-induced Ca2+ entry. delta-HCH failed to induce Ca2+ entry, rather it antagonized the HE-induced Ca2+ entry. Both HE and delta-HCH induced Ca2+ release from endoplasmic reticulum (ER) at treatment concentrations as low as 10 microM; at 50 microM, the former induced 5x as much Ca2+ release as the latter. The HE-induced Ca2+ release from the ER was antagonized using the IP3 receptor/channel blocker xestospongin C, suggesting that HE induces ER Ca2+ release through the IP3 receptor/channel pore. These results show that the effect of HE on cellular Ca2+ mimics that of mitogens such as epidermal and hepatocyte growth factors. They also provide insight into the similarities and differences between tumorigenic and non-tumorigenic OCs, in terms of the mechanisms and the extent of the [Ca2+]i increased by these agents.
Department of Environmental Toxicology, University of California, Davis, CA 95616, USA.
Mark E
ME
Hansen
Isaac N
IN
Pessah
Fumio
F
Matsumura
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D006534:Heptachlor Epoxide / Q000633:toxicity*; D001556:Hexachlorocyclohexane / Q000633:toxicity*; D007093:Imidazoles / Q000494:pharmacology; D007306:Insecticides / Q000633:toxicity*; D047028:Macrocyclic Compounds; D051379:Mice; D010080:Oxazoles / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007306:Insecticides; D047028:Macrocyclic Compounds; D010080:Oxazoles; D018808:Transcription Factor AP-1; C108644:xestospongin A; D006534:Heptachlor Epoxide; C086916:delta-hexachlorocyclohexane; D001556:Hexachlorocyclohexane; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D002118:Calcium