Dietary lycopene decreases the initiation of liver preneoplastic foci by diethylnitrosamine in the rat

Abstract

To test whether carotenoids can modulate the initiation of liver preneoplasia by diethylnitrosamine (DEN) or by 2‐nitropropane (2‐NP) in a sequential protocol of hepatocarcinogenesis, male weanling rats were fed for three or four weeks (respectively) diets containing β‐carotene, canthaxanthin, astaxanthin, or lycopene (300 mg/kg diet) or an excess of vitamin A (15,000 retinol equivalents/kg diet) or were treated intraperitoneally with 3‐methylcholan‐threne. During this period, all rats were injected intraperitoneally with the initiator carcinogen, either 2‐NP (6 times at 100 mg/kg body wt) or DEN (once at 100 mg/kg body wt). Three weeks after the termination of carotenoid or vitamin A feeding, the rats received 50 ppm of 2‐acetylaminofluorene in their diet for a two‐week period, in the middle of which they were subjected to two‐thirds partial hepatectomy, and were sacrificed one week later. γ‐Glutamyl transpeptidase‐and placental glutathione S‐transferase‐positive foci were detected in frozen‐cut liver sections by histochemical and histoimmunochemical techniques, respectively. None of the treatments tested had any influence on the number and size of preneoplastic liver foci induced by 2‐NP, despite a significant incorporation and persistence in the liver of the carotenoids, except astaxanthin, and of supplemental vitamin A. Feeding the rats lycopene significantly decreased the size of γ‐glutamyl transpeptidase‐ and glutathione S‐transferase‐positive foci induced by DEN (by 64% and 65%, respectively), as well as the fraction of liver volume occupied by foci (by 84% and 79%, respectively), but did not significantly reduce their number. The other carotenoids, including β‐carotene, exerted no significant effects on DEN‐induced preneoplasias. Lycopene does not appear to act through its antioxidant properties, but rather through its modulating effect on the liver enzyme activating DEN, cytochrome P‐450 2E1.