TY - JOUR
T1 - The co-mitogenic effects of various estrogens for TGF-α-induced DNA synthesis in cultured female rat hepatocytes
AU - Ni, Nan
AU - Yager, James D.
N1 - Funding Information:
We thank Dr Chuan-jun Li for providing consultation and help with the statistical analysis of the data and Dr Joanne Zurlo for helpful discussions and critical review of the manuscript. The authors also wish to acknowledge support from U.S. Public Health Service grant NC1 CA 36701. In addition, core facilities and shared-usee quipment were supported by NIEHS core grant ES 038 19 andT he Center for Alternatives to Animal Testing’s ‘In Vitro Toxicology Program’.
PY - 1994/9/15
Y1 - 1994/9/15
N2 - The synthetic estrogens ethinyl estradiol (EE) and mestranol (M) are weak complete hepatic carcinogens and potent tumor promoters. In vivo, EE and M cause a rapid but transient increase in liver growth. However, studies in cultured female rat hepatocytes indicate that EE is not a strong complete hepatic mitogen but rather enhances epidermal growth factor (EGF)-induced DNA synthesis and is thus classified as a co-mitogen (Yager, J.D., Zurlo, J. and Ni, N. (1991) Proc. Soc. Exptl. Biol. Med., 198, 667-674). The endogenous estrogen 17β-estradiol (E2) also exhibits co-mitogenic activity, enhancing the fraction of hepatocytes undergoing DNA synthesis induced by both EGF and transforming growth factor alpha (TGF-α) (Ni, N. and Yager, J.D. (1994) Hepatology, 19, 183-192). The objectives of the study reported here were: (1) to determine whether the co-mitogenic effects of EE and E2 extend to other synthetic estrogens including mestranol and diethylstilbestrol, and to α-zearalanol, a natural product with estrogenic activity; (2) to compare the co-mitogenic effects of endogenous estrogens including E2, estrone, estriol and the catechol metabolites 2- and 4-hydroxy-estradiol; and (3) to determine whether the conditioned medium from E2-treated hepatocytes has co-mitogenic activity. Female rat hepatocytes in primary culture were exposed to the various estrogens ± TGF-α and DNA synthesis was determined by measuring [3H]thymidine incorporation into extracted DNA. The results show that the co-mitogenic effects previously observed with EE and E2 also extend to all of these estrogens and to the E2 catechol metabolites. Although the co-mitogenic potency of these estrogens does not correlate with their reported affinities to the estrogen receptor, their estrogenicity appears necessary since the non-estrogenic metabolite 2-methoxyestradiol lacks co-mitogenic activity. In addition, enhancement of TGF-α-induced DNA synthesis by conditioned medium from E2-treated cells supports the notion that a metabolite mediates its co-mitogenic effect.
AB - The synthetic estrogens ethinyl estradiol (EE) and mestranol (M) are weak complete hepatic carcinogens and potent tumor promoters. In vivo, EE and M cause a rapid but transient increase in liver growth. However, studies in cultured female rat hepatocytes indicate that EE is not a strong complete hepatic mitogen but rather enhances epidermal growth factor (EGF)-induced DNA synthesis and is thus classified as a co-mitogen (Yager, J.D., Zurlo, J. and Ni, N. (1991) Proc. Soc. Exptl. Biol. Med., 198, 667-674). The endogenous estrogen 17β-estradiol (E2) also exhibits co-mitogenic activity, enhancing the fraction of hepatocytes undergoing DNA synthesis induced by both EGF and transforming growth factor alpha (TGF-α) (Ni, N. and Yager, J.D. (1994) Hepatology, 19, 183-192). The objectives of the study reported here were: (1) to determine whether the co-mitogenic effects of EE and E2 extend to other synthetic estrogens including mestranol and diethylstilbestrol, and to α-zearalanol, a natural product with estrogenic activity; (2) to compare the co-mitogenic effects of endogenous estrogens including E2, estrone, estriol and the catechol metabolites 2- and 4-hydroxy-estradiol; and (3) to determine whether the conditioned medium from E2-treated hepatocytes has co-mitogenic activity. Female rat hepatocytes in primary culture were exposed to the various estrogens ± TGF-α and DNA synthesis was determined by measuring [3H]thymidine incorporation into extracted DNA. The results show that the co-mitogenic effects previously observed with EE and E2 also extend to all of these estrogens and to the E2 catechol metabolites. Although the co-mitogenic potency of these estrogens does not correlate with their reported affinities to the estrogen receptor, their estrogenicity appears necessary since the non-estrogenic metabolite 2-methoxyestradiol lacks co-mitogenic activity. In addition, enhancement of TGF-α-induced DNA synthesis by conditioned medium from E2-treated cells supports the notion that a metabolite mediates its co-mitogenic effect.
KW - Co-mitogenesis
KW - Estrogens
KW - Promotion
KW - Rat hepatocytes
UR - http://www.scopus.com/inward/record.url?scp=0028050425&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0028050425&partnerID=8YFLogxK
U2 - 10.1016/0304-3835(94)90367-0
DO - 10.1016/0304-3835(94)90367-0
M3 - Article
C2 - 8076369
AN - SCOPUS:0028050425
SN - 0304-3835
VL - 84
SP - 133
EP - 140
JO - Cancer Letters
JF - Cancer Letters
IS - 2
ER -