Displacement of histamine from liver cells and cell components by ligands for cytochromes P450.
Intracellular histamine (HA) and cytochrome P450 monooxygenases (P450) each have been proposed as mediators of cell function, growth, and proliferation. The P450 family of heme enzymes is found in virtually all cells and generates, transforms, or inactivates steroids and other lipids that participate in cell regulation. We previously demonstrated a second messenger role for HA in blood platelets and the formation of a HA-P450 heme complex when exogenous HA was added to microsomes isolated from rat liver cells or to purified human P450 isozymes. Employing a radioimmunoassay, we now demonstrate that rat liver slices, microsomes derived from the livers of adult male rats and mast cell-deficient mice, and hepatoma cells, all contain endogenous HA. HA release from microsomes into the incubation medium, as determined by radioimmunoassay, is enhanced in the presence of carbon monoxide, steroids, and certain drugs, all agents that unite either directly with the iron atom or bind elsewhere within the heme cavity. Rat liver slices preincubated with (3)H-HA release labeled amine into the medium in the presence of those same ligands. These findings provide evidence of an in situ HA-P450 complex and offer further support that the imidazole, HA, is a physiological, intracellular modulator of cytochromes P450 in liver cells, and perhaps of these and other heme proteins in tissues in general.
Brandes
Lorne J
LJ
Department of Medicine, Faculty of Medicine, University of Manitoba, Canada. brandes@cc.umanitoba.ca
Queen
Gary M
GM
LaBella
Frank S
FS
D000735:Androstenedione / Q000494:pharmacology; D000818:Animals; D017332:Cetirizine / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D005473:Fluoxetine / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006632:Histamine / Q000737:chemistry / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008024:Ligands; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D046911:Macromolecular Substances; D008297:Male; D008407:Mast Cells / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
D008024:Ligands; D046911:Macromolecular Substances; D005473:Fluoxetine; D000735:Androstenedione; D006632:Histamine; D003577:Cytochrome P-450 Enzyme System; D017332:Cetirizine