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CELLULAR AND MOLECULAR

Autoregulation of McA-RH7777 Hepatoma Cell Proliferation by Histamine H₃ Receptors

INSERM, Laboratoire de Neurobiologie et Pharmacologie Moléculaire, Centre de Psychiatrie et Neurosciences, Paris, France

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 (B_max 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 -monofluoromethyl histidine increased cell proliferation (up to 60%), revealing a H₃R-mediated inhibition by endogenous HA. Moreover, exogenous HA inhibited the increase induced by -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.

Address correspondence to: Dr. Jean-Michel Arrang, Laboratoire de Neurobiologie et Pharmacologie Moléculaire, Centre de Psychiatrie et Neurosciences de l'INSERM, 2 ter rue d'Alésia, 75014 Paris, France. E-mail: jean-michel.arrang{at}inserm.fr