Further evidence for chemopreventive potential of beta-carotene against experimental carcinogenesis: Diethylnitrosamine-initiated and phenobarbital-promoted hepatocarcinogenesis is prevented more effectively by beta-carotenethan by retinoic acid

The comparative effectiveness of beta-carotene (BC) and retinoic acid (R4) was investigated against two-stage rat liver carcinogenesis initiated by a single injection of diethylnitrosamine (DEN, 200 mg/kg ip)followed by promo tion with phenobarbital (PB, 0.05%) in a basal diet. BC (500 mg/kg) or RA ( 200 mg/kg) was administered per os daily throughout the entire experiment, before the initiation, or during the promotional stage. Treatment with BC t hroughout the experiment or before initiation significantly reduced the inc idence (p < 0.01), multiplicity (p < 0.05), and size of visible subcapsular hepatocyte nodules (HNs) and reduced (p < 0.001 or 0.05) nodular volume as a percentage of liver volume. The results with RA were of lesser extent th an those observed with BC. There was a considerable depletion of hepatic BC and total vitamin A (retinol + ester) in HNs and nonnodular surrounding pa renchyma (NNSP) of rats subjected to the DEN-PB regimen than their control counterparts. Treatment with BC significantly elevated hepatic BC and total vitamin A contents in HNs and NNSP compared with DEN-PB control, and the e levation was proportional to the duration of BC treatment. Long-term BC or RA treatment elicited a substantial decrement in reduced glutathione conten t and gamma-glutamyltranspeptidase activity and an increment in cytochrome P-450 content and glutathione peroxidase and glutathione S-transferase acti vities in the HNs and NNSP, which were otherwise reversed in rats that rece ived DEN-PB treatment alone. Our results suggest that BC or R4 has the pote ntial to inhibit DEN-induced hepatocarcinogenesis through selective modulat ion of the antioxidant defense system and xenobiotic detoxification in the liver. It is also apparent that the beneficial effect of BC or R4 is primar ily exerted on the initiation phase and secondarily during the promotional stage of DEN-initiated rat liver carcinogenesis and that BC affords a bette r chemopreventive response than R4.