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.
Subject(s)
Adrenal Cortex/metabolism , Anticarcinogenic Agents/metabolism , Dehydroepiandrosterone/antagonists & inhibitors , Estrogen Antagonists/metabolism , Gene Expression Regulation, Enzymologic , Resorcinols/metabolism , Testosterone/antagonists & inhibitors , Adrenal Cortex/enzymology , Alkylation , Anticarcinogenic Agents/chemistry , Aromatase/chemistry , Aromatase/genetics , Aromatase/metabolism , Cell Line, Tumor , Cholesterol Side-Chain Cleavage Enzyme/chemistry , Cholesterol Side-Chain Cleavage Enzyme/genetics , Cholesterol Side-Chain Cleavage Enzyme/metabolism , Cytochrome P-450 Enzyme Inhibitors/chemistry , Cytochrome P-450 Enzyme Inhibitors/metabolism , Dehydroepiandrosterone/biosynthesis , Dietary Supplements , Estradiol/biosynthesis , Estrogen Antagonists/chemistry , Fatty Acids/chemistry , Fatty Acids/metabolism , Female , Humans , Male , Progesterone Reductase/antagonists & inhibitors , Progesterone Reductase/genetics , Progesterone Reductase/metabolism , Resorcinols/chemistry , Steroid 17-alpha-Hydroxylase/antagonists & inhibitors , Steroid 17-alpha-Hydroxylase/metabolism , Steroid 21-Hydroxylase/antagonists & inhibitors , Steroid 21-Hydroxylase/genetics , Steroid 21-Hydroxylase/metabolism , Testosterone/biosynthesisABSTRACT
BACKGROUND: Acetaminophen (paracetamol) is a widely used analgesic and antipyretic drug. Potential side effects are of public health concern, and liver toxicity from acute overdose is well known. More recently, a regular use of acetaminophen has been associated with an increased risk of hypertension. METHODS: We investigated effects of acetaminophen on steroidogenesis as a possible mechanism for the hypertensive action by using the human adrenocortical cell line, H295R. Cells were treated with 0.1, 0.5, and 1mM of acetaminophen for 24 hours, and secretion of steroids and gene expression of key steps in the steroidogenesis were investigated. RESULTS: Progesterone and aldosterone secretion were increased dose dependently, while secretion of 17α-OH-progesterone and cortisol as well as dehydroepiandrosterone and androstenedione was decreased. CYP17α-hydroxylase activity, assessed by the ratio 17α-OH-progesterone/progesterone, and CYP17-lyase activity, assessed by the ratio androstenedione/17α-OH-progesterone, were both dose-dependently decreased by acetaminophen. No effects were revealed on cell viability. Treatment of cells with 0.5mM of acetaminophen did not cause any effects on the expression of 10 genes in the steroidogenic pathways. CONCLUSIONS: The pattern of steroid secretion caused by acetaminophen can be explained by inhibition of CYP17A1 enzyme activity. A decreased secretion of glucocorticoids and androgens, as demonstrated by acetaminophen, would, in an in vivo situation, induce adrenocorticotropic hormone release via negative feedback in the hypothalamic-pituitary-adrenal axis and result in an upregulation of aldosterone secretion. Our results suggest a novel possible mechanism for acetaminophen-induced hypertension, which needs to be further elucidated in clinical investigations.
