Interaction of histamine and other bioamines with cytochromes P450: implications for cell growth modulation and chemopotentiation by drugs.
We have characterized microsomal and nuclear histamine sites, designated H(IC), through which this amine acts as an intracellular mediator of platelet aggregation and lymphocyte mitogenesis. A major proportion, at least, of the microsomal H(IC) sites are on cytochromes P450, an important family of microsomal enzymes that are present in all cells, but most abundant in the liver. These enzymes are involved in the metabolism of xenobiotics and natural substrates, including lipid hormones that modulate gene function and cell growth. We have shown that polyamines, hormones (including estrogen, testosterone and progesterone), antihormones (including tamoxifen and flutamide) and various antidepressants and antihistamines, all inhibit histamine binding to P450; we have postulated that, through binding to the heme moiety, intracellular histamine regulates cell function by modulating the catalytic activity of P450 enzymes, an action that may be perturbed by endogenous and exogenous substances. We now demonstrate that, in addition to histamine, melatonin and the biogenic amines dopamine, serotonin and noradrenaline bind to P450 isozymes and to cytochrome C. Thus, heme enzymes in general may represent common targets where multiple bioamines, hormones and drugs interact to influence cell function and growth.
LaBella
F S
FS
Department of Pharmacology and Therapeutics, Faculty of Medicine University of Manitoba, Winnipeg, Canada.
Brandes
L J
LJ
D000818:Animals; D001679:Biogenic Amines / Q000378:metabolism*; D002455:Cell Division; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D004357:Drug Synergism; D006632:Histamine / Q000378:metabolism*; D006801:Humans
D001679:Biogenic Amines; D006632:Histamine; D003577:Cytochrome P-450 Enzyme System