title: Wy-14,643 but not 2-ethylhexanol increases intracellular free calcium in cultured Kupffer cells.
abstract: Hypolipidemic drugs and phthalic ester plasticizers induce peroxisomes and cause hepatocellular carcinoma in rodents by mechanisms which remain unknown. Recent evidence from this laboratory suggests that many agents in this class of chemicals are uncouplers of mitochondrial oxidative phosphorylation both in vitro and in vivo. Uncoupling of oxidative phosphorylation decreases ATP required for ion pumps and could thereby indirectly increase intracellular free calcium. The goal of these experiments, therefore, was to compare the effect of the potent uncoupler and non-genotoxic carcinogen Wy-14,643 with the weaker agent 2-ethylhexanol on intracellular free calcium in cultured Kupffer cells. Kupffer cells, the resident hepatic macrophages, are activated by calcium and release a variety of mitogenic growth factors that may modulate cell proliferation. In this study, the cytosolic free calcium concentration in Fura-2-loaded cultured Kupffer cells was increased significantly from 78 +/- 11 to 838 +/- 112 nM following incubation with Wy-14,643 (1.25 mM). The increase in intracellular calcium due to Wy-14,643 was both time- and dose-dependent. At equimolar concentrations, ethylhexanol had no effect on intracellular calcium (65 +/- 20 nM). However, at higher concentrations (3 mM), ethylhexanol also increased intracellular calcium. These data suggest that elevation of intracellular calcium in Kupffer cells may be involved in the mechanism of action of this interesting class of non-genotoxic carcinogens.
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill 27599-7365.
authors.forename: T
authors.initials: T
authors.lastname: Hijioka
authors.forename: B J
authors.initials: BJ
authors.lastname: Keller
authors.forename: R G
authors.initials: RG
authors.lastname: Thurman
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D000441:Hexanols / Q000494:pharmacology*; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D000924:Anticholesteremic Agents; D000441:Hexanols; D011743:Pyrimidines; C006253:pirinixic acid; D002118:Calcium; C034017:2-ethylhexanol