Down regulation of epidermal growth factor receptors in rat hepatocytes treated with clofibric acid.
The effect of clofibric acid (CA), a peroxisome proliferator and a non-genotoxic hepatocarcinogen was investigated on epidermal growth factor (EGF) receptors in hepatocytes of female Sprague-Dawley rats treated at a dose of 9000 ppm in a diet for up to 13 weeks. Hepatocyte plasma membranes were isolated in Weeks 1 and 13, and assayed with [125I]EGF. The binding of EGF to the hepatocyte plasma membranes was reduced in Week 1 as a result of decreased number of low-affinity receptors. The fall of binding capacity was further evident in Week 13, which was associated with decreased numbers of both high- and low-affinity receptors. The equilibrium dissociation constant remained unchanged either in Week 1 or 13. These results were in agreement with previous observations of a decreased hepatocyte response to mitogens after prolonged treatment with CA. This suggested that the CA-associated liver tumor promoting effect is related to its ability to decrease the number of EGF receptors and the resultant aberrant growth environment.
Tanaka
K
K
Development Research Laboratories, Banyu Pharmaceutical Co., Ltd., Osato, Saitama, Japan.
Yoshida
E
E
Ishizaki
H
H
Hasegawa
T
T
Matsumoto
H
H
Ikemoto
F
F
Doi
K
K
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002995:Clofibric Acid / Q000008:administration & dosage / Q000633:toxicity*; D015536:Down-Regulation; D066246:ErbB Receptors / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008830:Microbodies / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D000924:Anticholesteremic Agents; D007457:Iodine Radioisotopes; D002995:Clofibric Acid; D066246:ErbB Receptors