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A dual and opposite effect of Calendula officinalis flower extract: Chemoprotector and promoter in a rat hepatocarcinogenesis model

Abstract:

Calendula officinalis extracts have protective and cytotoxic effects. We previously reported the dual activity of C. officinalis in primary rat hepatocyte cultures treated with N-nitrosodiethylamine. At nM concentrations it was anti-genotoxic while at μM concentrations it exhibited genotoxic effects. Here we tested the activity of Calendula officinalis in vivo in male Fischer 344 rats initiated with N-nitrosodiethylamine, promoted with 2-acetylaminofluorene, and 70% partially hepatectomized. Liver γ-glutamyl-transpeptidase positively altered hepatocyte foci 25 days after initiation were our end point. The protective effect of C. officinalis started at 0.1 mg/kg concentration, increased at 0.5 mg/kg and reached its maximum at 2.5 mg/kg, when it decreased the area and number of altered foci by 55% and 49%, respectively, in comparison with rats treated only with carcinogen. At 5 mg/kg the number and area of altered hepatocyte foci were still lower, but almost reached the figures of carcinogen-treated rats. Ten and 20 mg/kg doses produced a notorious increment in the area and number of altered hepatic foci, and at 40 mg/kg of extract the increment was 40% and 53%, respectively. Additionally, when 2-acetylaminofluorene was substituted by a 40 mg/kg C. officinalis extract, a promoting effect was observed with increments of 175% and 266% in area and number of altered hepatocyte foci with respect to controls. When N-nitrosodiethylamine was substituted by 40 mg/kg of extract, the latter did not show initiator activity. In summary, we showed a protecting activity of C. officinalis at low doses, but doses above 10 mg/kg increased altered hepatocyte foci. This dual effect is an example of the phenomenon of hormesis. Furthermore, 40 mg/kg of dry weight extract administered instead of 2-acetylaminofluorene induced a clear promoting activity. These in vivo results are similar and consistent with those reported by us in primary rat liver cell cultures. © Georg Thieme Verlag KG Stuttgart.