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.

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.