Document Detail


Orotic acid, nucleotide-pool imbalance, and liver-tumor promotion: a possible mechanism for the mitoinhibitory effects of orotic acid in isolated rat hepatocytes.
MedLine Citation:
PMID:  1531940     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
This study was designed to determine the possible mechanism by which orotic acid exerts its mitoinhibitory effect on rat hepatocytes in primary culture. Orotic acid inhibited, dose-dependently DNA synthesis in hepatocytes induced by epidermal growth factor, transforming growth factor alpha, hepatocyte growth factor, acidic fibroblast growth factor, or plasma from rats exposed to various liver cell-proliferative stimuli, such as two-thirds partial hepatectomy, lead nitrate, cyproterone acetate, ethylene dibromide, or a diet deficient in choline. Further, orotic acid inhibited DNA synthesis even when added 24 h after the hepatocytes were primed with transforming growth factor alpha. Taken together, these results suggested that the target site may not be at the level of the growth-factor receptor and receptor-mediated early events. In a preliminary experiment, orotic acid inhibited the expression of the ribonucleoside diphosphate reductase gene. Exposure to orotic acid results in an imbalance in nucleotide pools characterized by an increase in uridine nucleotides and a decrease in adenosine nucleotides. It is hypothesized that this imbalance in nucleotide pools inhibits the expression of the ribonucleoside diphosphate reductase gene and, therefore, is a likely target for the mitoinhibitory effect of orotic acid.
Authors:
S Manjeshwar; A Sheikh; G Pichiri-Coni; P Coni; P M Rao; S Rajalakshmi; P Pediaditakis; G Michalopoulos; D S Sarma
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  52     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  1992 Apr 
Date Detail:
Created Date:  1992-04-15     Completed Date:  1992-04-15     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2078s-2081s     Citation Subset:  IM    
Affiliation:
Department of Pathology, University of Toronto, Ontario, Canada.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Division / drug effects
DNA / biosynthesis*
Dose-Response Relationship, Drug
Epidermal Growth Factor / antagonists & inhibitors
Fibroblast Growth Factors / antagonists & inhibitors
Growth Substances
Hepatocyte Growth Factor
Liver / drug effects*,  pathology
Liver Neoplasms, Experimental / chemically induced*
Male
Mitosis / drug effects
Orotic Acid / pharmacology*
Rats
Rats, Inbred F344
Ribonucleoside Diphosphate Reductase / antagonists & inhibitors
Transforming Growth Factor alpha / antagonists & inhibitors
Grant Support
ID/Acronym/Agency:
CA37077/CA/NCI NIH HHS; CA43632/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Growth Substances; 0/Transforming Growth Factor alpha; 62031-54-3/Fibroblast Growth Factors; 62229-50-9/Epidermal Growth Factor; 65-86-1/Orotic Acid; 67256-21-7/Hepatocyte Growth Factor; 9007-49-2/DNA; EC 1.17.4.1/Ribonucleoside Diphosphate Reductase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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