4-Hexylresorcinol Exhibits Different Characteristics to Estrogen

Abstract

4-Hexylresorcinol (4HR) has been used as a food additive and antiseptic. The aim of this study was to evaluate whether the application of 4HR in breast cancer cells and ovariectomized rats showed estrogen-like effects. MCF-7 and SK-BR-3 cells were treated by solvent, 1–100 µM bisphenol-A (BPA), or 1–100 µM 4HR, respectively. 3-(4, 5-Dimethylthiazole-2-yl)- 2,5-diphenyltetrazolium bromide (MTT) assay and Western blot for extracellular signal-regulated kinase-1/-2 (ERK1/2), phosphorylated ERK1/2 (p-ERK1/2), estrogen receptor-α (ERα), and ERβ were done. As an in vivo study, ovariectomized rats (n = 15) received solvent, 125 mg/kg of 4HR, or 10 µg of 17-β estradiol via daily subcutaneous injection for 7 days. Blood samples were obtained for evaluation of prolactin levels. Pituitary glands and uteruses were biopsied for histological evaluation and Western blot analysis. Compared with the control group, the application of 4HR decreased the proliferation of MCF-7 and SK-BR-3 cells, while the application of BPA increased (p < 0.05). The application of BPA increased the expression of ERα, ERβ, and p-ERK1/2, but 4HR did not change the expression of ERα, ERβ, or p-ERK1/2 in MCF-7 cells. In an animal model, the 4HR group showed similar levels of ERα, ERβ, and prolactin expression in the pituitary gland compared to the solvent only group, while the estradiol group showed higher levels. Serum prolactin levels were similar between the 4HR and solvent only groups. Taken together, 1–100 µM 4HR did not show BPA-like behavior in MCF-7 cells, and 125 mg/kg of 4HR daily subcutaneous injection for 7 days did not demonstrate estradiol-like effects in ovariectomized rats. Collectively, 4HR has no estrogen-like effects on both ERα-positive cells and estrogen-deficient rat models.

Effects of 4-Hexylresorcinol on Craniofacial Growth in Rats

“…The 4HR is used as a food additive because of its antibrowning effect [21], and it is suspected to be pseudo-estrogen [24]. However, 4HR administration in the ovariectomized rat model did not show an estrogenic effect [25]. In this study, the serum level of estrogen was not significantly different between the EF and CF groups (p > 0.05; Figure 3B), and 4HR showed HDACi activity in HUVECs [23].…”

Increased Level of Vascular Endothelial Growth Factors by 4-hexylresorcinol is Mediated by Transforming Growth Factor-β1 and Accelerates Capillary Regeneration in the Burns in Diabetic Animals

“…According to a previous study [31], 4HR was suspected to be xenoestrogen. Although estrogen can increase angiogenesis [32], the effect and signaling pathway of 4HR are different from those of estrogen [33]. Accordingly, TGF-β1 is a key cytokine in skin wound healing, and 4HR increased its level of expression in this study.…”

The effect of 4-hexylresocinol administration on SCC-9 cells: mass spectrometric identification of proteins and cDNA microarray analysis

“…1 ) and cDNA microarray assay (Table 2 ). Although this study focused on SCC-9 cells and OSCC, we also observed the inhibitory action of 4HR on breast carcinoma cell lines [ 18 ]. Besides, 4HR inhibited cell proliferation-related genes including cyclin C and other RNA polymerases by cDNA microarray assay (Table 2 ).…”

“…As for the potential use of 4HR as an anti-cancer drug, we have to mention the previous toxicology and carcinogenesis studies demonstrating that the oral administration of 4HR in doses up to 650–1000 mg/kg to animals unaffected their survival [ 9 ]. In the Zebra fish study, the administration of 4HR in doses up to 1 mM (194 μg/ml) is not teratogenic to the developing embryo [ 18 ]. The effective dose of 4HR, used for injections of carcinoma-grafted nude mice, was 10 mg/kg body weight, i.e., two orders of magnitude less, and caused no toxic side effects in our in vivo experiments [ 12 ].…”