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.

A S Randi

doi:10.1093/toxsci/kfg253

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 h, and ODC activity and spermine and putrescine content after 18 and 24 h, while maximum 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.

Highlights

Hexachlorobenzene (HCB) is one of the most widespread environmental pollutants
We have reported that HCB changes epidermal growth factor (EGF) affinity for its membrane receptor, induces EGFR internalization and stimulates EGFR-tyrosine kinase activity (Randi et al, 1998, 2003)
The acute exposure assay was carried out at 6, 12, 18, and 24 h posttreatment. This dose of HCB was chosen based on our recent results that showed that the maximum increase in rat liver EGFR-tyrosine kinase activity was reached at this concentration (Randi et al, 2003)

Summary

Introduction

Hexachlorobenzene (HCB) is one of the most widespread environmental pollutants. the use of HCB was discontinued in most countries in the 1970s, it is still released into the environment as a byproduct of the manufacture of other polychlorinated organocompounds (Courtney, 1979). A relevant signal associated with cell growth, differentiation, and malignant transformation is the induction of a group of immediate-early (IE) genes that encode the transcriptional activator proteins c-Fos, c-Jun, and c-Myc (Schutte et al, 1989; Vogt and Bos, 1989). Ornithine decarboxylase activity can be regulated by phosphorylation, confirming the pivotal role of ODC in cell-signaling pathways triggered at the cell surface (Desiderio et al, 1998). As HCB is a nongenotoxic tumor promoter, it is reasonable to ask whether it can initiate the signals associated with cell growth and transformation. We have reported that HCB changes epidermal growth factor (EGF) affinity for its membrane receptor, induces EGFR internalization and stimulates EGFR-tyrosine kinase activity (Randi et al, 1998, 2003). Other subcellular mechanistic studies have shown that HCB exposure induced alterations in intercellular gap junctional communication in female rat liver (Mally and Chipman, 2002; Plante et al, 2002)

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