All-trans and 9-cis retinoic acids, retinol and [beta]-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 β-carotene (βC) 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 βC (βC group) or corn oil (CO group, controls). Hepatocyte nodule incidence was reduced (P < 0.05) in βC group (46%), but not (P > 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 (P < 0.05) between CO group (44 ± 9) and 9cRA (11 ± 4), ROL (7 ± 3) and βC (4 ± 2) groups, except for AtRA group (27 ± 9; P > 0.05). Number/cm2 liver section, mean area (mm2) and percent liver section area occupied by total (persistent + remodeling) placental glutathione S-transferase (GST-P) positive PNL was reduced (P < 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 βC (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 < 0.05) in 9cRA (92 ± 1), ROL (96 ± 1) and βC (93 ± 1) groups, but not (P > 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 < 0.05) cell proliferation and no differences (P > 0.05) in apoptosis. DNA damage [comet length (μm)] was reduced (P < 0.05) in ROL (87.9 ± 2.6) and βC (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 βC 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 βC actions, while inhibition of DNA damage relates to ROL and βC actions.