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
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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