Research article
Chemopreventive effects of β-ionone and geraniol during rat hepatocarcinogenesis promotion: distinct actions on cell proliferation, apoptosis, HMGCoA reductase, and RhoA

https://doi.org/10.1016/j.jnutbio.2009.12.007Get rights and content

Abstract

Chemopreventive activities of the dietary isoprenoids β-ionone (βI) and geraniol (GOH) were evaluated during the promotion phase of hepatocarcinogenesis. Over 5 consecutive weeks, rats received daily 16 mg/100 g body weight (b.w.) of βI (βI group), 25 mg/100 g b.w. of GOH (GOH group), or only corn oil (CO group, controls). Compared to the CO group, the following was observed: only the βI group showed a decrease in the mean number of visible hepatocyte nodules (P<.05); βI and GOH groups had reduced mean number of persistent preneoplastic lesions (pPNLs) (P<.05), but no differences regarding number of remodeling PNL (rPNLs) were observed; only the βI group exhibited smaller rPNL size and percentage of liver sections occupied by pPNLs (P<.05), whereas the GOH group displayed a smaller percentage of liver sections occupied by rPNLs (P<.05); a trend was observed in the βI group, which showed reduced cell proliferation of pPNLs (P<.10), and the GOH group had increased apoptosis in pPNLs and rPNLs (P<.05); only the βI group displayed reduced total plasma cholesterol concentrations (P<.05) and increased hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase mRNA levels (P<.05); only the GOH group had lower hepatic membrane RhoA protein levels (P<.05); both the βI- and GOH-treated groups had higher hepatic concentrations of βI and GOH, respectively (P<.05). Given these data, βI and GOH show promising chemopreventive effects during promotion of hepatocarcinogenesis by acting through distinct mechanism of actions: βI may inhibit cell proliferation and modulate HMGCoA reductase, and GOH can induce apoptosis and inhibit RhoA activation.

Introduction

The consumption of bioactive compounds in food has been previously demonstrated to correlate with reduction in cancer risk [1]. Dietary isoprenic derivatives such as β-ionone (βI), a cyclic isoprenoid present in grapes and wine [2], and geraniol (GOH), an acyclic monoterpene present in lemon and lemongrass [3], represent a promising class of chemopreventive agents [4].

The anticarcinogenic actions of βI and GOH have been described mostly in vitro [5]. Among the few in vivo studies, βI inhibits melanoma [6], breast cancer [7], and colon [8] cancer development, while GOH inhibits growth of pancreatic adenocarcinomas [9]. Both isoprenoids inhibit hepatic preneoplastic lesions (PNLs) when administered continuously during the initiation and selection/promotion phases of hepatocarcinogenesis [10], [11].

One proposed chemopreventive mechanism of isoprenoids is the suppression of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase activity, which is frequently increased and deregulated in preneoplastic and neoplastic tissues [5]. This suppression limits farnesyl and geranylgeranyl pyrophosphates [12], which are important for prenylation of proto-oncogenes such as RhoA [12], [13], thereby inhibiting cell proliferation and inducing apoptosis [14], [15], [16].

In the present study, the chemopreventive activities of βI and GOH were investigated when administered during the promotion phase of the “resistant hepatocyte” (RH) model of hepatocarcinogenesis. Parameters that were evaluated include PNL development, cell proliferation, apoptosis, total plasma cholesterol concentration, HMGCoA reductase mRNA levels, RhoA activation, and hepatic concentrations of βI and GOH.

Section snippets

Chemicals

βI [4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3(E)-buten-2-one, 95%], GOH (trans-3,7-dimethyl-2, 6-octadien-1-ol, 98%), 2-acetylaminofluorene (2-AAF), 5-bromo-2′-deoxyuridine (BrdU), diethylnitrosamine (DEN), and 3,3′-diaminobenzidine were purchased from Sigma (St. Louis, MO, USA); commercial diet was purchased from Purina (Campinas, Brazil); corn oil (CO), Mazola (São Paulo, Brazil); polyclonal anti-placental glutathione S-transferase (GST-P) rabbit antibody was purchased from Medical and

Body and liver weights, incidence and mean number of visible hepatocyte nodules

Table 1 presents the data on body and liver weights and incidence and mean number per rat of visible hepatocyte nodules. No differences (P>.05) were observed between the different experimental groups regarding the final body weights and absolute and relative liver weights, which indicates that βI and GOH did not cause toxicity at the dosages that were used. Additionally, no differences (P>.05) were observed between the different experimental groups regarding incidence of nodules. When compared

Discussion

Previous studies have demonstrated the chemopreventive activity of βI [10] and GOH [11] when administered continuously during the initiation and selection/promotion phases of the RH model of hepatocarcinogenesis. Due to the experimental design of these studies, the observed protective effects were attributed to the isoprenoid-mediated modulation of carcinogen metabolism. Since reducing the initiation phase to a zero level is impossible, the most effective intervention would be at the promotion

Acknowledgments

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). The authors are indebted to Miss Silvania M.P. Neves for providing the care and maintenance of the animals.

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