Changes in protein and mRNA levels of growth factor/growth factor receptors in rat livers after administration of phenobarbitone or methylclofenapate.
The effects of phenobarbitone and methylclofenapate were studied on the expression of growth factor and growth factor receptors in livers of male Wistar rats. The major findings were: (1) a significant reduction in epidermal growth factor receptor (EGFR) protein observed with both treatments, and (2) levels of EGFR transcripts were only slightly decreased with both compounds. The reduction in the receptor level therefore does not occur via regulation of transcription. Mannose-6-phosphate receptors (M6PR, also called insulin-like growth factor II receptor) and M6PR transcripts remained unchanged in both experimental groups. Hepatocyte growth factor receptor (HGFR) transcripts were also unchanged in both experimental groups. Transcript levels of transforming growth factor-beta 1 (TGF-beta 1) were lower in both treatment groups compared with the control; the reduction was significant in the methylclofenapate group. This may have relevance to the finding by others that nafenopin, another peroxisome proliferator, suppresses rat hepatocyte apoptosis. Another finding of general interest was that the three "housekeeping genes", namely albumin, actin and glyceraldehyde-3-phosphate dehydrogenase, were influenced by both treatments thus limiting their use as controls for gel loading. The adaptation of a growth regulatory mechanism via EGFR and its ligands may provide conditions such that cells with aberrant growth control have a selective growth advantage over normal cells thus promoting tumorigenesis.
Garcia-Allan
C
C
Safety of Medicines Department, Zeneca Pharmaceuticals, Macclesfield, Cheshire, UK.
Loughlin
J
J
Orton
T
T
Lord
P
P
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002992:Clofenapate / Q000008:administration & dosage*; D066246:ErbB Receptors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006133:Growth Substances / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000008:administration & dosage*; D011506:Proteins / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017527:Receptor, IGF Type 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D006133:Growth Substances; D011506:Proteins; D012333:RNA, Messenger; D017527:Receptor, IGF Type 2; D017978:Receptors, Growth Factor; D002992:Clofenapate; D066246:ErbB Receptors; D010634:Phenobarbital