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 beta-carotene (betaC) 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 betaC (betaC group) or corn oil (CO group, controls). Hepatocyte nodule incidence was reduced (P < 0.05) in betaC 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 betaC (4 +/- 2) groups, except for AtRA group (27 +/- 9; P > 0.05). Number/cm(2) liver section, mean area (mm(2)) 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 betaC (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 betaC (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 (mum)] was reduced (P < 0.05) in ROL (87.9 +/- 2.6) and betaC (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 betaC 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 betaC actions, while inhibition of DNA damage relates to ROL and betaC actions.
Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
Elaine Maria
EM
de Almeida Vasconcelos Fonseca
Carlos Eduardo Andrade
CE
Chagas
Rogério Pietro
RP
Mazzantini
Renato
R
Heidor
Thomas Prates
TP
Ong
Fernando Salvador
FS
Moreno
D000077556:Alitretinoin; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018890:Chemoprevention; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects*; D005982:Glutathione Transferase / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015994:Incidence; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011230:Precancerous Conditions / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D014212:Tretinoin / Q000494:pharmacology; D014801:Vitamin A / Q000494:pharmacology; D019207:beta Carotene / Q000494:pharmacology*
D000970:Antineoplastic Agents; D000975:Antioxidants; D019207:beta Carotene; D014801:Vitamin A; D000077556:Alitretinoin; D014212:Tretinoin; D005982:Glutathione Transferase