Modifying effect of Siraitia grosvenori extract on piperonyl butoxide-promoted hepatocarcinogenesis in rats.
To examine the possible modifying effect of the extract of Siraitia grosvenori (SGE), a naturally occurring antioxidative agent, on piperonyl butoxide (PBO)-promoted hepatocarcinogenesis, male F344 rats were administered a single intraperitoneal injection of N-diethylnitrosamine (DEN) as an initiator followed by administration of a diet containing 2% PBO for 7 weeks with or without SGE (1,000 ppm) in the drinking water. To enhance cellular proliferation, all animals underwent two-thirds partial hepatectomy 1 week after the commencement of PBO administration. Pretreatment with SGE was also applied to the PBO + SGE group for 2 weeks prior to DEN initiation. Liver immunohistochemistry revealed that although the PBO-mediated increase in the number of glutathione S-transferase placental form (GST-P)-positive foci and proliferating cell nuclear antigen-positive cells remained unaltered with SGE coadministration, the area of the GST-P-positive foci was increased. On the contrary, real-time RT-PCR showed that coadministration of SGE increased hepatic GST and glutathione peroxidase (GSH-Px) antioxidant activities and mRNA expression levels of the phase II enzymes that are known to be transcriptionally up-regulated through the Nrf 2-Keap1-antioxidant responsive element (ARE) as well as the phase III enzymes. Furthermore, measurement of thiobarbituric acid-reactive substances showed a decrease in lipid peroxidation by SGE coadministration. The results suggest that SGE may exert hepatic antioxidant activity by up-regulating the genes under the control of the Nrf 2-Keap1-ARE transcriptional machinery; however, this activity was neither effective nor sufficient for suppression of PBO-promoted early hepatocarcinogenesis.
Yasuno
Hironobu
H
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo, Japan. shiperfnoru@yahoo.co.jp
Nishimura
Jihei
J
Dewa
Yasuaki
Y
Muguruma
Masako
M
Takabatake
Masayoshi
M
Murata
Yuji
Y
Shibutani
Makoto
M
Mitsumori
Kunitosh
K
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D019662:Cucurbitaceae / Q000737:chemistry*; D020869:Gene Expression Profiling; D005979:Glutathione Peroxidase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010882:Piperonyl Butoxide; D010936:Plant Extracts / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000975:Antioxidants; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase; D010882:Piperonyl Butoxide