Journal Article

All-<i>trans</i> and 9-<i>cis</i> retinoic acids, retinol and β-carotene chemopreventive activities during the initial phases of hepatocarcinogenesis involve distinct actions on glutathione <i>S</i>-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

in Carcinogenesis

Volume 26, issue 11, pages 1940-1946
Published in print November 2005 | ISSN: 0143-3334
Published online June 2005 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgi161
All-trans and 9-cis retinoic acids, retinol and β-carotene chemopreventive activities during the initial phases of hepatocarcinogenesis involve distinct actions on glutathione S-transferase positive preneoplastic lesions remodeling and DNA damage

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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.

Keywords: 2-AAF, 2-acetylaminofluorene; AI, apoptosis index; AtRA, all-trans retinoic acid; βC, β-carotene; CO, corn oil; DMSO, dimethylsulfoxide; GST-P, placental glutathione S-transferase; HCC, hepatocellular carcinoma; H&E, hematoxylin–eosin; LI, labeling index; N, normal; 9cRA, 9-cis retinoic acid; PBS, phosphate buffered saline; PCNA, proliferating cell nuclear antigen; PH, partial hepatectomy; PNL, preneoplastic lesions; RH, resistant hepatocyte; ROL, retinol

Journal Article.  5429 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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