Farnesol and geraniol chemopreventive activities during the initial phases of hepatocarcinogenesis involve similar actions on cell proliferation and DNA damage, but distinct actions on apoptosis, plasma cholesterol and HMGCoA reductase

Chemopreventive activities of farnesol (FOH) and geraniol (GOH) were evaluated during the initial phases of hepatocarcinogenesis. Rats received during eight consecutive weeks 25 mg/100 g body weight FOH (FOH group) or GOH (GOH group), or only corn oil (CO group, controls). Incidence (%) and mean number of visible hepatocyte nodules/animal were inhibited in FOH group (13% and 4 +/- 1; P < 0.05), but not in GOH group (42% and 18 +/- 17, P > 0.05), compared to CO group (100% and 42 +/- 17). Mean area (mm2) and % liver section area occupied by total hepatic placental glutathione S-transferase positive preneoplastic lesions (PNLs) were reduced in FOH group (0.09 +/- 0.06; 2.8 +/- 1.3; P < 0.05) compared to CO group (0.18 +/- 0.12; 10.0 +/- 2.8), while in GOH group only the mean area of these PNL was reduced (0.11 +/- 0.09; P < 0.05), but not the % liver section area occupied by them (5.1 +/- 1.1; P > 0.05). Compared to CO group, FOH and GOH groups showed reduced (P < 0.05) PNL cell proliferation and DNA damage, but only GOH group showed increased PNL apoptosis (P < 0.05). FOH group, but not GOH group, presented reduced (P < 0.05) total plasma cholesterol levels and increased (P < 0.05) hepatic levels of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase mRNA, compared to CO group. No differences (P > 0.05) were observed between CO, FOH and GOH regarding hepatic levels of farnesoid X activated receptor (FXR) protein. Results indicate that FOH and GOH could represent promising chemopreventive agents against hepatocarcinogenesis. Inhibition of cell proliferation and DNA damage relate to both isoprenoids' anticarcinogenic actions while induction of apoptosis specifically relates to GOH protective actions. Inhibition of HMGCoA reductase activity could be associated with FOH, but not GOH anticarcinogenic actions. FXR does not seem to be involved in the isoprenoids' chemopreventive activities.     

Geranylgeraniol and beta-ionone inhibit hepatic preneoplastic lesions, cell proliferation, total plasma cholesterol and DNA damage during the initial phases of hepatocarcinogenesis, but only the former inhibits NF-kappaB activation

Chemopreventive activities of the isoprenoids geranylgeraniol (GGO) and beta-ionone (BI) were evaluated during initial phases of hepatocarcinogenesis. Rats received 8 or 16 mg/100 g body wt GGO (GGO8 and GGO16 groups) or BI (BI8 and BI16 groups), or only corn oil (CO group, controls) daily for 7 weeks. Incidence (%) and the mean number of visible hepatocyte nodules/animal were inhibited in the GGO8 (64% and 21 +/- 40), GGO16 (33% and 3 +/- 5), BI8 (50% and 13 +/- 34) and BI16 (42% and 9 +/- 19) groups compared with the CO group (100% and 34 +/- 51) (P < 0.05, except for the GGO8 group). Number/cm(2) liver section, mean area (mm(2)) and % liver section area occupied by persistent hepatic placental glutathione S-transferase positive preneoplastic lesions (PNL) were reduced in the GGO8 (11 +/- 9; 0.26 +/- 0.35; 2.7 +/- 3.0), GGO16 (6 +/- 6; 0.18 +/- 0.16; 0.9 +/- 0.9), BI8 (9 +/- 5; 0.13 +/- 0.20; 1.1 +/- 1.2) and BI16 (8 +/- 6; 0.08 +/- 0.09; 0.6 +/- 0.4) groups compared with the CO group (26 +/- 18; 0.29 +/- 0.34; 7.0 +/- 5.5) (P < 0.05). GGO16 and BI16 groups showed smaller visible hepatocyte nodules, reduced PNL cell proliferation and total plasma cholesterol levels compared with the CO group (P < 0.05), but did not show any differences (P > 0.05) in PNL apoptosis. DNA damage expressed as comet length (microm) was reduced in the GGO8 (96.7 +/- 1.5), GGO16 (94.2 +/- 1.5), BI8 (97.1 +/- 1.1) and BI16 (95.1 +/- 1.5) groups compared with the CO group (102.1 +/- 1.7) (P < 0.05). In comparison with normal animals, the CO group animals showed increased (P < 0.05) nuclear levels of nuclear factor kappa B (NF-kappaB) p65 subunit in hepatic cells, which were decreased (P < 0.05) in the GGO16 group animals. Anticarcinogenic actions of these isoprenoids seem to follow a dose-response relationship. Results indicate that GGO and BI could be represented as promising chemopreventive agents against hepatocarcinogenesis. Inhibition of cell proliferation and DNA damage seems to be important for the anticarcinogenic actions of isoprenoids, while the inhibition of NF-kappaB activation seems to be specifically related to GGO actions.