Prevention of colonic aberrant crypt foci by dietary feeding of garcinol in male F344 rats

The modifying effects of dietary feeding of a polyisoprenylated benzophenon e, garcinol, isolated from Garcinia indica fruit rind on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investig ated in male F344 rats. We also assessed the effects of garcinol on prolife rating cell nuclear antigen (PCNA) index in ACF and activities of detoxifyi ng enzymes of glutathione S-transferase (GST) and quinone reductase (QR) in liver. In addition, we examined the effects of garcinol on 12-O-tetradecan oylphorbol-13-acetate-induced O-2(-) generation in differentiated human pro myelocytic HL-60 cells and lipopolysaccharide (LPS)- and interferon (IFN)-g amma-induced nitric oxide (NO) generation in mouse macrophage RAW 264.7 cel ls. Western blotting analysis of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression was done in LPS- and IFN-gamma-treated mouse macrophage RAW 264.7 cells. Rats were given subcutaneous injections of AOM (15 mg/kg body wt) once a week for 3 weeks to induce ACF, They also received the experimental diet containing 0.01 or 0.05% garcinol for 5 week s, starting 1 week before the first dosing of AOM, AOM exposure produced 97 +/- 15 ACF/rat at the end of the study (week 5), Dietary administration of garcinol caused significant reduction in the frequency of ACF: 72 +/- 15 ( 26% reduction, P < 0.01) at a dose of 0.01% and 58 +/- 8 (40% reduction, P < 0.001) at a dose of 0.05%. Garcinol administration significantly lowered PCNA index in ACF. Feeding of garcinol significantly elevated liver GST and QR activities. In addition, garcinol could suppress O-2(-) and NO generati on and expression of iNOS and COX-2 proteins. These findings might suggest possible chemopreventive ability of garcinol, through induction of liver GS T and QR, inhibition of O-2(-) and NO generation and/or suppression of iNOS and COX-2 expression, on colon tumorigenesis.