Journal Article

Phenobarbital at low dose exerts hormesis in rat hepatocarcinogenesis by reducing oxidative DNA damage, altering cell proliferation, apoptosis and gene expression

Anna Kinoshita, Hideki Wanibuchi, Keiichirou Morimura, Min Wei, Jun Shen, Susumu Imaoka, Yoshihiko Funae and Shoji Fukushima

in Carcinogenesis

Volume 24, issue 8, pages 1389-1399
Published in print August 2003 | ISSN: 0143-3334
Published online August 2003 | e-ISSN: 1460-2180 | DOI:
Phenobarbital at low dose exerts hormesis in rat hepatocarcinogenesis by reducing oxidative DNA damage, altering cell proliferation, apoptosis and gene expression

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Our recent research indicated that phenobarbital (PB) may inhibit the development of N-diethylnitrosamine (DEN)-initiated pre-neoplastic lesions at low doses in a rat liver medium-term bioassay (Ito test), while high doses exhibit promoting activity. This raises the question of whether treatment with low doses of PB might reduce cancer risk. For clarification, male 6-week-old F344 rats were treated with PB at doses of 0, 2, 15 and 500 p.p.m. in the diet for 10 or 33 weeks after initiation of hepatocarcinogenesis with DEN. In a second, short-term experiment, animals were given PB at doses of 2, 4, 15, 60 and 500 p.p.m. for 8 days. Formation of glutathione S-transferase placental form (GST-P) positive foci and liver tumors was inhibited at 2 p.p.m. Generation of oxidative DNA damage marker, 8-hydroxy-2′-deoxyguanosine (8-OHdG), cellular proliferation within the areas of GST-P positive foci and apoptosis in background liver parenchyma were suppressed. Suppression of 8-OHdG formation by PB at low dose might be related to the enhanced mRNA expression of 8-OHdG repair enzyme, oxoguanine glycosylase 1 (Ogg1). Moreover, as detected by cDNA microarray analysis, PB treatment at low dose enhanced mRNA expression of glutamic acid decarboxylase (GAD65), an enzyme involved in the synthesis of gamma-aminobutyric acid (GABA), and suppressed MAP kinase p38 and other intracellular kinases gene expression. On the contrary, when PB was applied at a high dose, GST-P positive foci numbers and areas, tumor multiplicity, hydroxyl radicals and 8-OHdG levels were greatly elevated with the increase in CYP2B1/2 and CYP3A2 mRNA, protein, activity and gene expression of GST, nuclear tyrosine phosphatase, NADPH- cytochrome P-450 reductase and guanine nucleotide binding protein G(O) alpha subunit. These results indicate that PB exhibits hormetic effect on rat hepatocarcinogenesis initiated with DEN by differentially altering cell proliferation, apoptosis and oxidative DNA damage at high and low doses.

Keywords: CYP2B1/2, CYP3A2 and CYP2C11, 2B1/2, isoenzymes of cytochrome P-450, respectively; DEN, N-diethylnitrosamine; DMPO, 5,5-dimethyl-1-pyrroline-N-oxide; DMPO–OH, spin adduct of DMPO and hydroxyl radicals; ESR, electron spin resonance; GAPDH, glyceraldehyde-3-P dehydrogenase; GABA, gamma-aminobutyric acid; GAD65, glutamic acid decarboxylase; GST-P, glutathione S-transferase placental form; HCC, hepatocellular carcinoma; HPLC, high performance liquid chromatography; Ogg1, 8-oxoguanine DNA glycosylase 1; 8-OHdG, 8-hydroxy-2′-deoxy- guanosine; OR, NADPH cytochrome P-450 reductase; PB, phenobarbital; P-450, cytochrome P-450; PCNA, proliferating cell nuclear antigen; ssDNA, single-stranded DNA

Journal Article.  7669 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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