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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 1 mM 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 17a-OH-progesterone and cortisol as well as dehydroepiandrosterone and androstenedione was decreased. CYP17a-hydroxylase activity, assessed by the ratio 17a-OHprogesterone/ progesterone, and CYP17-lyase activity, assessed by the ratio androstenedione/17a-OH-progesterone, were both dosedependently decreased by acetaminophen. No effects were revealed on cell viability. Treatment of cells with 0.5 mM 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. [ABSTRACT FROM AUTHOR]