Lack of Inhibitory Effects of Coumaperine from Pepper on the Promotion Stage of Chemical Hepatocarcinogenesis in the Rat

Abstract

We previously indicated that coumaperine isolated from pepper can protect against the initiation of rat hepatocarcinogenesis. In the present study, potential modifying effects of coumaperine on post-initiation promotion stage were examined, using a medium term rat liver bioassay (Ito test). F344 rats were given a single intraperitoneal injection of diethylnitrosamine (200 mg/kg body wt.) and subjected to two-thirds partial hepatectomy at week 3. Commencing 2 weeks from the start, coumaperine at doses of 0, 2, 10, 50 mg/kg body wt. was given to the rats for 6 weeks. All surviving animals were killed at week 8, and their livers were immunohistochemically examined for expression of glutathione S-transferase placental form (GST-P) and transforming growth factor-α (TGF-α). The numbers and areas of GST-P positive foci in rats given 2, 10 or 50 mg/kg coumaperine were comparable to the control values. There were also no significant intergroup differences regarding numbers and areas of TGF-α positive foci. This study suggested that coumaperine does not inhibit liver carcinogenesis in the promotion stage.

Possible tumor development from double positive foci for TGF‐alpha and GST‐P observed in early stages on rat hepatocarcinogenesis

“…We previously reported less frequent TGF‐α‐positive foci seen within GST‐P‐positive foci at week 8 in this bioassay, ( 8 ) the frequency of double positive foci being about 10% of the total. ( 8,9 ) TGF‐α is synthesized as a 160 kDa membrane spanning precursor, and the more active 50 amino acid mature form released from the cell surface by proteolytic cleavage can bind to the epidermal growth factor receptor (EGF‐R) and act as a potent hepatocyte mitogen with a role in rodent and human hepatocarcinogenesis. ( 10–13 ) Expression of TGF‐α has been demonstrated in neoplasms as well as hepatic altered foci, ( 14,15 ) but little is known about timing or stage of TGF‐α expression in hepatic altered foci and changes in the frequency with development into tumors.…”