Antifibrogenic effects of tamoxifen in a rat model of periportal hepatic fibrosis.
OBJECTIVE
It has been reported that tamoxifen may affect hepatoma cell growth in vitro by suppressing transforming growth factor beta-1 (TGF-beta1) expression, suggesting that tamoxifen might also retard fibrogenesis. Thus, we examined whether tamoxifen might suppress TGF-beta1 expression and consequently inhibit the process of hepatic fibrosis in vivo.


METHODS
To induce periportal hepatic fibrosis, 50 male adult Sprague-Dawley rats were injected with 0.62 mmol/kg of allyl alcohol, intraperitoneally, twice a week for 8 weeks. Hepatic fibrosis scores, intrahepatic collagen levels and plasma TGF-beta1 expression levels were evaluated in three groups of 10 rats orally administered tamoxifen at 1, 5 and 10 mg/kg, respectively, and in 20 controls. Messenger RNAs (mRNAs) encoding TGF-beta1 and TGF-beta receptors in liver tissue were semiquantified using reverse transcriptase polymerase chain reaction.


RESULTS
Hepatic fibrosis scores decreased progressively as the dose of tamoxifen increased, resulting in a significant change in rats treated with tamoxifen at 10 mg/kg compared with controls (P=0.018). Intrahepatic collagen content was significantly less in the group treated with tamoxifen at 10 mg/kg compared with the control (P=0.045). Plasma TGF-beta1 levels were also significantly lower in rats treated with tamoxifen at 10 mg/kg compared with controls (P=0.007). All three concentrations of tamoxifen tested decreased the expression levels of hepatic TGF-beta1 mRNA and type I TGF-beta receptor (TGF-beta RI) mRNA to similar extents.


CONCLUSIONS
Tamoxifen seems to inhibit the process of hepatic fibrosis dose-dependently by suppressing the transcription of TGF-beta1 and TGF-beta RI in an experimental model of periportal hepatic fibrosis.
Department of Internal Medicine, University of Inje College of Medicine, Seoul Paik Hospital, Seoul, Republic of Korea.
Soo Hyung
SH
Ryu
Young-Hwa
YH
Chung
Jae Kyun
JK
Lee
Jeong A
JA
Kim
Jung Woo
JW
Shin
Myoung Kuk
MK
Jang
Neung Hwa
NH
Park
Han Chu
HC
Lee
Yung Sang
YS
Lee
Dong Jin
DJ
Suh
D000818:Animals; D003094:Collagen / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020005:Propanols / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D018709:Statistics, Nonparametric; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use; D053773:Transforming Growth Factor beta1 / Q000097:blood*
D017931:DNA Primers; D020005:Propanols; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D013629:Tamoxifen; C006463:allyl alcohol; D003094:Collagen