title: The antiproliferative potency of histamine antagonists correlates with inhibition of binding of [3H]-histamine to novel intracellular receptors (HIC) in microsomal and nuclear fractions of rat liver.
abstract: Previously, we identified in rat liver microsomes, low (microM) affinity histamine receptors (HIC), associated with antiestrogen binding sites (AEBS). N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl (DPPE), a potent AEBS ligand, is a specific HIC antagonist. Through binding HIC, newly-formed intracellular histamine mediates, and DPPE inhibits, human platelet aggregation. We now provide evidence that histamine, mobilized from cytoplasmic stores, is a mediator of the mitogenic response to concanavalin A in mouse spleen cells. DNA synthesis and intracellular histamine levels are decreased over time by the histidine decarboxylase inhibitor, alpha-fluoromethylhistidine. For DPPE, H1 and H2 antagonists, rank order of potency to inhibit [3H]-histamine binding to HIC in rat liver microsomes correlates with antiproliferative potency. DPPE also competes for [3H]-histamine binding at low and high affinity sites in rat liver nuclei (IC50 approximately 2 microM). Thus, histamine may mediate growth through two intracellular subtypes of HIC.
authors.affiliation: Department of Medicine, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: L J
authors.initials: LJ
authors.lastname: Brandes
authors.forename: J R
authors.initials: JR
authors.lastname: Davie
authors.forename: F
authors.initials: F
authors.lastname: Paraskevas
authors.forename: B
authors.initials: B
authors.lastname: Sukhu
authors.forename: R P
authors.initials: RP
authors.lastname: Bogdanovic
authors.forename: F S
authors.initials: FS
authors.lastname: LaBella
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004965:Estrogen Antagonists / Q000378:metabolism; D006632:Histamine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology*; D008099:Liver / Q000648:ultrastructure*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D010647:Phenyl Ethers / Q000378:metabolism / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011969:Receptors, Histamine H1 / Q000378:metabolism*
chemical_list: D004965:Estrogen Antagonists; D006633:Histamine Antagonists; D010647:Phenyl Ethers; D010975:Platelet Aggregation Inhibitors; D011969:Receptors, Histamine H1; C054284:alpha-fluoromethylhistamine; D006632:Histamine; D004247:DNA; C043062:tesmilifene