All-trans and 9-cis retinoic acids, retinol and b-carotene chemopreventive activities during the initial phases of hepatocarcinogenesis involve distinct actions on glutathione S-transferase positive preneoplastic lesions remodeling and DNA damage

Chemopreventive activities of all-trans retinoic acid (AtRA), 9-cis retinoic acid (9cRA), retinol (ROL) and b-carotene (bC) were evaluated during hepatocarcinogenesis. Rats received 1 mg/100 g body wt AtRA (AtRA group), 9cRA (9cRA group), ROL (ROL group), 7 mg/100 g body wt bC (bC group) or corn oil (CO group, controls). Hepatocyte nodule incidence was reduced (P 5 0.05) in bC group (46%), but not (P 4 0.05) in AtRA (92%), 9cRA (92%) and ROL (82%) groups, compared with the CO group (100%). Multiplicity of these preneoplastic lesions (PNL) was different (P5 0.05) between CO group (44 9) and 9cRA (11 4), ROL (7 3) and bC (4 2) groups, except for AtRA group (27 9; P 4 0.05). Number/cm liver section, mean area (mm) and percent liver section area occupied by total (persistent þ remodeling) placental glutathione S-transferase (GST-P) positive PNL was reduced (P 5 0.05) in AtRA (107 13; 0.12 0.06; 13.9 3.9), 9cRA (71 12; 0.12 0.06; 6.8 2.2), ROL (96 13; 0.11 0.22; 6.8 2.0) and bC (106 13; 0.08 0.03; 10.8 2.5) groups compared with CO group (166 14; 0.18 0.09; 28.6 5.2). Percent of remodeling GST-P positive PNL was increased (P 5 0.05) in 9cRA (92 1), ROL (96 1) and bC (93 1) groups, but not (P4 0.05) in AtRA group (90 2), compared with the CO group (86 1). Compared with the CO group, all groups present in PNL reduced (P 5 0.05) cell proliferation and no differences (P 4 0.05) in apoptosis. DNA damage [comet length (mm)] was reduced (P 5 0.05) in ROL (87.9 2.6) and bC (89.2 4.0) groups, but not in AtRA (94.8 4.1) and 9cRA (94.2 1.5) groups, compared with the CO group (100.4 3.9). AtRA, 9cRA, ROL and bC presented chemopreventive activities against hepatocarcinogenesis. These involve inhibition of cell proliferation, but not induction of apoptosis. Increased remodeling of GST-P positive PNL relates to 9cRA, ROL and bC actions, while inhibition of DNA damage relates to ROL and bC actions.