Inhibition of ornithine decarboxylase activity but not expression of the gene by cimetidine in intestinal mucosal cells.
Cimetidine has been shown to inhibit normal and carcinoma cell growth but the mechanism of the antiproliferative action is incompletely understood. The current study determined the influence of cimetidine on ornithine decarboxylase (ODC) activity, which is the initial rate-limiting enzyme in polyamine biosynthesis, in rat duodenal mucosa and IEC-6 cells (a line of normal rat intestinal crypt cells). Rats were fasted 22 hr before the various treatments and ODC activity was measured in scraped duodenal mucosa. Administration of pentagastrin and epidermal growth factor (EGF) and refeeding fasted rats significantly increased ODC activity in duodenal mucosa. Cimetidine completely inhibited increases in ODC activity in the mucosa stimulated by pentagastrin and EGF, but not by refeeding. Ranitidine and H1-receptor antagonist chlorpheniramine had similar inhibitory effects on ODC activity induced by gastrin. In cultured IEC-6 cells, cimetidine caused a linear and significant inhibition of the stimulation of ODC activity in response to pentagastrin, EGF, 5% dialyzed fetal bovine serum (FBS) and asparagine. ODC messenger RNA (mRNA) levels in IEC-6 cells were significantly increased after exposure to 5% dialyzed FBS and asparagine. Although cimetidine almost completely prevented the induction of ODC activity in IEC-6 cells exposed to serum or asparagine, the increases in ODC mRNA levels were not inhibited by the compound.(ABSTRACT TRUNCATED AT 250 WORDS)
Wang
J Y
JY
Department of Physiology and Biophysics, University of Tennessee College of Medicine, Memphis, USA.
McCormack
S A
SA
Viar
M J
MJ
Johnson
L R
LR
D000818:Animals; D001216:Asparagine / Q000494:pharmacology; D001769:Blood; D002455:Cell Division / Q000187:drug effects; D002744:Chlorpheniramine / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology*; D004386:Duodenum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005215:Fasting; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006632:Histamine / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009955:Ornithine Decarboxylase / Q000235:genetics; D065108:Ornithine Decarboxylase Inhibitors; D010418:Pentagastrin / Q000494:pharmacology; D011899:Ranitidine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D065108:Ornithine Decarboxylase Inhibitors; D002744:Chlorpheniramine; D004815:Epidermal Growth Factor; D001216:Asparagine; D002927:Cimetidine; D006632:Histamine; D011899:Ranitidine; D009955:Ornithine Decarboxylase; D010418:Pentagastrin