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ToxSci Advance Access published online on November 4, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg253
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received July 25, 2003; accepted September 16, 2003
© 2003 Society of Toxicology

Carcinogenicity

Hexachlorobenzene Induced Early Changes in Ornithine Decarboxylase and Protein Tyrosine Kinase Activities, Polyamines and c-Myc, c-Fos and c-Jun Proto-Oncogenes in Rat Liver

Andrea S. Randi 1, Susana Hernández 2, Laura Alvarez 1, Marcela Sánchez 3, Marta Schwarcz 4, and Diana L. Kleiman de Pisarev 1*

1 Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, CP 1121, Buenos Aires, Argentina
2 Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, CP 1121, Buenos Aires, Argentina; Facultad de Medicina, Universidad Abierta Interamericana, CP 1147, Buenos Aires, Argentina
3 Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, CP 1121, Buenos Aires, Argentina; Ciclo Básico Común, Universidad de Buenos Aires, CP 1053, Buenos Aires, Argentina
4 Ciclo Básico Común, Universidad de Buenos Aires, CP 1053, Buenos Aires, Argentina; Facultad de Medicina, Universidad Abierta Interamericana, CP 1147, Buenos Aires, Argentina

* To whom correspondence should be addressed. E-mail: dkleiman{at}fmed.uba.ar.


  Abstract

Hexachlorobenzene (HCB) is a lipophilic chemical compound that is widely distributed in the environment. HCB is known to cause liver tumors in experimental animals. In the present study the in vivo effect of HCB treatment on ornithine decarboxylase (ODC) and protein tyrosine kinase (PTK) activities, free polyamine content and c-Myc, c-Fos and c-Jun protein levels in rat liver were investigated. HCB (1000 mg/kg body weight) increased hepatic immunodetectable c-Myc, c-Fos and c-Jun levels after 6 hours and ODC activity and spermine and putrescine content after 18 and 24 hours, while maximun stimulation of PTK activity occurred at 12 h. PTK and ODC activities varied in a dose-dependent manner. The time-course of c-Myc, c-Fos and c-Jun protein levels was different for each proto-oncogene. They were all elevated at the second day of treatment, while only c-Fos and c-Jun remained elevated after 10 days of HCB exposure. These data jointly suggest that the increase in ODC activity may be the consequence of proto-oncogene induction. The alterations in PTK activity suggest that the growth factor signal transduction pathway may be involved in the regulation of the proto-oncogene levels or/and ODC activity. The decrease in PTK activity after the first day, even in the presence of {alpha}-D-Difluoromethylornithine (DFMO), an inhibitor of ODC activity, suggests that it is not regulated by polyamines. These results may be relevant to the early molecular events involved in HCB tumor promoter activity in rat liver.

Key Words: hexachlorobenzene, rat liver, ODC activity, PTK activity, polyamine content, proto-oncogene levels .


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