Effect of in vivo administered hexachlorobenzene on epidermal growth factor receptor levels, protein tyrosine kinase activity, and phosphotyrosine content in rat liver.
In the present study, the effects of hexachlorobenzene (HCB) on epidermal growth factor receptor (EGFR) content of liver microsomes and plasma membrane, and on EGFR-tyrosine kinase activity in the microsomal fraction were investigated. In addition, we studied the parameters of the tyrosine kinase signalling pathway such as protein tyrosine kinase (PTK) activity and phosphotyrosine content in microsomal and cytosolic protein. To determine whether the observed alterations were correlated with a manifestation of overt toxicity, a single very low dose of HCB (1mg/kg body wt) and two much higher doses (100 and 1000 mg/kg body wt), the highest being toxicologically significant in that it reduced serum thyroxine (T(4)) and inhibited uroporphyrinogen decarboxylase (URO-D) (EC 4.1.1.37) activity, were tested. Our results demonstrated that liver microsomes of rats treated with HCB had higher levels of EGFR than untreated rats; treated rats also had less EGFR present in hepatocyte plasma membrane fractions than did untreated rats. HCB altered the phosphotyrosine content and protein phosphorylation of some microsomal and cytosolic proteins in a biphasic dose-response relationship. At the low dose, phosphorylation and phosphotyrosine content of several microsomal proteins were increased; however, these effects were diminished or reversed at the higher doses. Our results suggest that chronic HCB treatment produces a down-regulation of the EGFR and a dose-dependent increase in EGFR-tyrosine kinase activity in the microsomal fraction. This effect may contribute to the alteration of membrane and cytosolic protein tyrosine phosphorylation. The level of sensitivity encountered in our studies is extraordinary, occurring at 1/10 to 1/1000 the doses of HCB known to cause other toxicological lesions.
Randi
Andrea S
AS
Departamento de Bioqui;mica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 5to piso, CP 1121, Buenos Aires, Argentina.
Sancovich
Horacio A
HA
Ferramola de Sancovich
Ana M
AM
Loaiza
Andrea
A
Kölliker Frers
Rodolfo A
RA
Spinelli
Fernanda
F
Kleiman de Pisarev
Diana L
DL
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D017252:CD3 Complex / Q000097:blood; D015704:CD4 Antigens / Q000097:blood; D066246:ErbB Receptors / Q000378:metabolism*; D005659:Fungicides, Industrial / Q000633:toxicity*; D006581:Hexachlorobenzene / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats
D017252:CD3 Complex; D015704:CD4 Antigens; D005659:Fungicides, Industrial; D019000:Phosphotyrosine; D006581:Hexachlorobenzene; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases