Minoxidil: Mechanisms of Action on Hair Growth

A.G. Messenger; J. Rundegren


The British Journal of Dermatology. 2004;150(2) 

In This Article

Minoxidil Sulphation

The antihypertensive activity of minoxidil is due to rapid relaxation of vascular smooth muscle by its sulphated metabolite, minoxidil sulphate.[12,13] The conversion of minoxidil to minoxidil sulphate is catalysed by sulphotransferase enzymes. Minoxidil sulphotransferase activity was initially demonstrated in rat liver[12] and has since been found in human liver,[14] platelets[15] and epidermal keratinocytes,[16] as well as in mouse vibrissae follicles,[17] rat pelage and vibrissae follicles and rat epidermal keratinocytes.[18,19] In scalp skin of stumptail macaques, sulphotransferase activity is largely localized in the hair follicle.[20] In rat pelage and vibrissae follicles, immunoreactivity for minoxidil sulphotransferase was seen in the outer root sheath.[18]

Five human cytosolic sulphotransferase genes have been discovered to date. They encode three classes of enzymes responsible for sulphating phenols and catecholamines, oestrogens and hydroxysteroids.[21] In human liver extracts, sulphation of minoxidil is catalysed by at least four sulphotransferases. Biochemical evidence for minoxidil sulphation by two phenol sulphotransferases has been found in human scalp skin[22] and Dooley[21] reported finding mRNA expression for four sulphotransferases in human epidermal keratinocytes. There are interindividual variations in scalp sulphotransferase activity and this correlates with the level in platelets.[22] In a clinical setting, scalp sulphotransferase activity was higher in men who responded to minoxidil compared with those who did not respond.[23]

Minoxidil sulphate is one of several chemically unrelated drugs which cause opening of plasma membrane adenosine triphosphate (ATP)-sensitive potassium channels (KATP channels), and its relaxant effect on vascular smooth muscle is mediated through this mechanism.[24,25] KATP channels are heteromultimers composed of a small subunit that belongs to the inwardly rectifying potassium channel superfamily (KIR6.1 or KIR6.2), and a large sulphonylurea receptor (SUR1, SUR2A or SUR2B) that binds sulphonylureas and ATP and belongs to the ATP-binding cassette (ABC) superfamily.[26] SUR1/KIR6.2 KATP channels are found in pancreatic and neuronal tissue, whereas SUR2A/KIR6.2 and SUR2B/KIR6.1 (or KIR6.2) form the cardiac and vascular smooth muscle KATP channels, respectively. Potassium channel openers act through binding to the sulphonylurea receptor moiety.[26]

KATP channels are widely distributed in a variety of tissue and cell types, including cells of the heart, pancreas, vascular smooth muscle and the central nervous system, where they couple intracellular metabolic changes to the electrical activity of the plasma membrane.[27] These potassium channels sense the metabolic state of the cell -- channel opening is inhibited by ATP when energy levels are high and is activated when energy stores are depleted.[28] The consequence of KATP status depends on the cell and tissue type. For example, in pancreatic ß cells, KATP channels are involved in regulating insulin secretion. In vascular smooth muscle cells the vasodilating action of potassium channel openers is due to membrane hyperpolarization and a reduction in Ca2+ influx, which reduces the electrical excitability of the cell. It has also been suggested that potassium channel activity is required for early-stage cell proliferation by G1 progression of the cell cycle.[29] Minoxidil was shown to increase DNA synthesis, whereas glibenclamide suppressed DNA synthesis in rat primary hepatocyte cultures.[30] Hepatocyte potassium currents were augmented by minoxidil and attenuated by glibenclamide.