Suppressed Sex Hormone Biosynthesis by Alkylresorcinols: A Possible Link to Chemoprevention

Abstract

Alkylresorcinols (ARs, 5-n-alkylresorcinols) are amphiphilic phenolic lipids in whole grain rye and wheat, with a long odd-numbered carbon chain. A preventive effect of whole grain diet on sex hormone-dependent cancers has been recognized, but the active component(s) or mechanisms are not known. We have investigated the effects of the ARs C15:0, C19:0, and C21:0, individually and in combination, on steroid hormone production by using the human adrenocortical cell line H295R. Decreased synthesis of dehydroepiandrosterone (DHEA), testosterone, and estradiol was demonstrated at low concentrations of C15:0 and C19:0. There were no indications of additive effects on steroid secretion from the combined treatment with equimolar concentrations of the three ARs. Gene expressions of CYP21A2, HSD3B2, and CYP19A1 were downregulated and CYP11A1 was upregulated by the ARs. The results on gene expression could not explain the effects on steroidogenesis, which may be due to direct effects on enzyme activities, such as inhibition of CYP17A1. Our results demonstrate suppressed synthesis of testosterone and estradiol by ARs suggesting a novel mechanism for ARs in the chemoprevention of prostate and breast cancer.

An Overview of Alkylresorcinols Biological Properties and Effects

“…In the study of Oskarsson and Ohlsson [ 72 ] carried out on the human adrenocortical cell line H295R, the nontoxic concentrations of C15 : 0 and C19 : 0 ARs directly affected the steroidogenesis; namely, they reduced the synthesis of testosterone and decreased the secretion of estradiol, cortisol, and aldosterone. The authors proposed that the decline in the secretion of the hormones could appear due to the inhibition of the activity of CYP17 enzyme, which is in charge of the conversion of pregnenolone to 17 α -OH-pregnenolone and of progesterone to 17a-OH-progesterone.…”

“…Along with ARs leading to decreased plasma estrogen levels, the generally high dietary fiber intake was reported to be associated with the lower risk of breast cancer as well [ 78 , 79 ]. Besides the mechanism described earlier, ARs, as highly lipophilic molecules, are proposed to affect steroid hormone production through the accumulation in tissues enriched in lipids, such as adipose tissue, testis, ovaries, and adrenal cortex, which are in charge of steroidogenesis [ 72 ].…”

General Health Benefits and Pharmacological Activities of Triticum aestivum L.

“…Importantly, the separated alkylresorcinols had an inhibitory impact on the breast cancer cell line examined that was at least 800% greater than the routinely used chemotherapy, adriamycin. In another study to examine the mechanism of alkylresorcinols [ 99 ], it has been found that alkylrespocinols suppressed the expression of CYP21A2, HSD3B2, and CYP19A1 genes, while increased the expression of CYP11A1. The impacts on steroidogenesis could not be explained by gene expression data, which might be attributable to direct effects on enzyme activities, such as suppression of CYP17A1.…”

Long-Term Whole Grain Wheat and Rye Intake Reflected by Adipose Tissue Alkylresorcinols and Breast Cancer: A Case-Cohort Study

“…Adipose tissue in the breast is one of the main sites of sex hormone production in post-menopausal women [86,87]. Short alkylresorcinol homolog exposure of adipose tissue through storage in its adipocytes or in postprandial blood [43] may alter sex hormone synthesis by promoting the synthesis of progestogens from cholesterol and suppressing downstream metabolism of progestogens and estradiol, as shown in vitro [78]. A high concentration of these sex hormones is strongly associated with risk of breast cancer [88].…”

“…In a secondary analysis, we also assessed the risk of developing breast cancer using short alkylresorcinol homologs (C17:0, C19:0 or C21:0) as exposure in Crude biomarker models and Multivariate-adjusted biomarker models. This was because alkylresorcinol homologs shorter than C21:0 have been shown to suppress synthesis of sex hormones [78] and because the C17:0/C21:0 ratio is potentially affected by C17:0, C21:0, or both.…”