Autoregulation of McA-RH7777 Hepatoma Cell Proliferation by Histamine H3Receptors
Open Access
- 12 May 2008
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Journal of Pharmacology and Experimental Therapeutics
- Vol. 326 (2), 406-413
- https://doi.org/10.1124/jpet.107.135368
Abstract
Previous studies have suggested that histamine (HA) acts as an autocrine growth factor. We have explored the modulation of cell proliferation by HA using McA-RH7777 hepatoma cells. High l-histidine decarboxylase (HDC) expression and HA synthesis were found in McA-RH7777 cells. Whereas extracellular HA reached submicromolar concentrations, intracellular levels were very low, indicating that HA was secreted by the cells. McA-RH7777 cells also express H3-receptor (H3R) transcripts and proteins. Reverse transcriptase-polymerase chain reaction analysis detected only transcripts for the long isoform. Immunocytochemistry performed with a selective H3R antibody showed that most cells were immunoreactive. H3R binding sites (Bmax ∼30 fmol/mg protein) were identified when [125I] iodoproxyfan binding was displaced by the agonist imetit. High-affinity binding also occurred at cytochrome P450 enzymes. This binding was not inhibited by HA, H3R agonists, or by a nonimidazole H3R antagonist but was displaced by imidazole H3R antagonists or by ketoconazole, a imidazole-containing cytochrome inhibitor. HA inhibited proliferation of McA-RH7777 hepatoma cells. The absence of uptake system, its much higher potency at H3Rs, and its low intracellular levels suggested that HA interacted with H3Rs rather than cytochromes. In agreement, both imidazole H3R antagonists, a nonimidazole H3R antagonist, and the HDC inhibitor α-monofluoromethyl histidine increased cell proliferation (up to ∼60%), revealing a H3R-mediated inhibition by endogenous HA. Moreover, exogenous HA inhibited the increase induced by α-FMH or H3R antagonists with a nanomolar potency. In conclusion, our findings show that HA regulates proliferation of McA-RH7777 hepatoma cells by interacting with autoinhibitory H3Rs.Keywords
This publication has 36 references indexed in Scilit:
- The histamine H4 receptor: A novel modulator of inflammatory and immune disordersPharmacology & Therapeutics, 2007
- G-protein-coupled receptors and cancerNature Reviews Cancer, 2007
- BF2.649 [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, Hydrochloride], a Nonimidazole Inverse Agonist/Antagonist at the Human Histamine H3 Receptor: Preclinical PharmacologyJournal of Pharmacology and Experimental Therapeutics, 2006
- CATALYTIC RECEPTORSBritish Journal of Pharmacology, 2006
- Ligands for histamine H3receptors modulate cell proliferation and migration in rat oxyntic mucosaBritish Journal of Pharmacology, 2002
- Displacement of histamine from liver cells and cell components by ligands for cytochromes P450Journal of Cellular Biochemistry, 2002
- Expression of histidine decarboxylase and cellular histamine-like immunoreactivity in rat embryogenesis.Journal of Histochemistry & Cytochemistry, 1995
- Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptorNature, 1983
- Selective inhibitors of biosynthesis of aminergic neurotransmittersNature, 1978
- Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reactionBiochemical Pharmacology, 1973