Interactive binding at cytochrome P-450 of cell growth regulatory bioamines, steroid hormones, antihormones, and drugs.
The virtually universal family of P-450 isozymes contribute to the regulation of cell growth by modulating the levels of steroids and other lipid messengers for cytoplasmic and nuclear processes, including gene expression. In microsomes from rat liver cells, the concentration ( approximately 1 nmole/mg protein) of cytochromes P-450 approximates that of intracellular binding sites (K(d) 1.0-50 microM) for histamine. The potencies of certain therapeutic drugs to inhibit catalytic activity of, and histamine binding to, cytochromes P-450 in vitro were previously shown by us to be predictive of relative propensities to modulate tumor growth in rodents. Also, we demonstrated that growth-regulating polyamines potently interact with histamine at P-450. We now show that several classes of steroid hormones, antiestrogens, and antiandrogens, as well as various arylalkylamine drugs, all potently inhibit (3)H-histamine binding to cytochrome P-450 (K(i) values: testosterone 0.28 microM, progesterone 0.56 microM, flutamide 1.7 microM, tamoxifen 9.0 microM). Furthermore, all the various hormone and drug ligands are mutually inhibitory in their binding to cytochrome P-450; e.g., K(i) values of androstenedione and progesterone, to inhibit imipramine binding to P-450 (determined by spectral analysis), are 11 nM and 26 nM, respectively. The K(i) value of imiprimine to inhibit binding of androstenedione to P-450 is 3.5 microM. We estimate the total P-450 content in microsomes to be greater in male than in female rats and correlated with the number of binding sites for histamine, but not for steroids and drugs that appear to be more selective for P-450 isozymes. Thus, for at least some isozymes, the homeostatic role of the monooxygenases may be governed by histamine, modulated by endogenous ligands, and perturbed by many foreign molecules.
LaBella
F S
FS
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0W3, Canada.
Queen
G M
GM
Brandes
L J
LJ
D000818:Animals; D001665:Binding Sites; D001679:Biogenic Amines / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D012739:Gonadal Steroid Hormones / Q000378:metabolism / Q000494:pharmacology; D006632:Histamine / Q000378:metabolism; D007099:Imipramine / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008024:Ligands; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013053:Spectrophotometry; D013250:Steroid Hydroxylases / Q000378:metabolism; D013256:Steroids / Q000378:metabolism
D001679:Biogenic Amines; D012739:Gonadal Steroid Hormones; D007527:Isoenzymes; D008024:Ligands; D004364:Pharmaceutical Preparations; D013256:Steroids; D006632:Histamine; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C022657:steroid hormone 6-beta-hydroxylase; D007099:Imipramine