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Carcinogenesis Advance Access originally published online on June 23, 2005
Carcinogenesis 2005 26(11):1940-1946; doi:10.1093/carcin/bgi161
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Carcinogenesis vol.26 no.11 © Oxford University Press 2005; all rights reserved.

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

Elaine Maria de Almeida Vasconcelos Fonseca, Carlos Eduardo Andrade Chagas, Rogério Pietro Mazzantini, Renato Heidor, Thomas Prates Ong and Fernando Salvador Moreno *

Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil

* To whom correspondence should be addressed at: Departamento de Alimentos e Nutrição Experimental, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Bloco 14, Avenue Prof. Lineu Prestes 580, 05508-900, São Paulo, SP, Brazil. Tel: +00 55 (11) 3091 3630; Fax: +00 55 (11) 3815 4410; Email: RMORENO{at}USP.BR

Chemopreventive activities of all-trans retinoic acid (AtRA), 9-cis retinoic acid (9cRA), retinol (ROL) and ß-carotene (ßC) 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 ßC (ßC group) or corn oil (CO group, controls). Hepatocyte nodule incidence was reduced (P < 0.05) in ßC 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 ßC (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 ßC (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 ßC (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 ßC (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 ßC 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 ßC actions, while inhibition of DNA damage relates to ROL and ßC actions.


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