Jump to comment:

• Glibenclamide for acne?
  Richard G Fiddian-Green
  Published on: 12 January 2007

• Published on: 12 January 2007

  Glibenclamide for acne?

  • Richard G Fiddian-Green, FRCS, FACS

  Dear Editor,

  Drugs that cause acne include those that can impair oxidative phosphorylation such as antidepressants, anti-seizure medications, and cyclosporin which closes the permeability transition pore on mitochondrial membranes. Impairment of oxidative phosphorylation should be accompanied by a fall in cutaneous tissue pH and energy charge. Drugs that aggravate acne include testosterone, corticosteroids, and an...

  Show More

  Dear Editor,

  Drugs that cause acne include those that can impair oxidative phosphorylation such as antidepressants, anti-seizure medications, and cyclosporin which closes the permeability transition pore on mitochondrial membranes. Impairment of oxidative phosphorylation should be accompanied by a fall in cutaneous tissue pH and energy charge. Drugs that aggravate acne include testosterone, corticosteroids, and anabolic steroids. Might they do so by causing a fall in cutaneous tissue pH and/or energy charge?

  The superficial layers of skin must be alkalotic because they exist in an hypocarbic hyperoxic environment (1). In decreasing the magnitude of the protonmotive force this should down-regulate ATP resynthesis by oxidative phosphorylation and up-regulate that by glycolysis alone. As the temperature of skin is also lower than core temperature and ATP yield increases as the temperature increases skin is at a metabolic disadvantage. Fetal skin, which does not scar, is much better off. It is exposed to a much higher pCO2, 40 mmHg, the core temperature and a much lower pO2, one less likely to generate free radicals. Fetal skin has, therefore, a metabolic advantage over normal skin. Increasing the pCO2 to which skin is exposed, decreasing the pO2 and increasing its temperature might all be of benefit in acne sufferers because of an improvement in tissue energetics. This is not a practical solution.

  In myocytes testosterone induces cytoprotection by activation [opening] of mitoKATP channel (2). It appears to do so by decreasing myocardial contractility and hence workload. Myocardial dysfunction, commonly achieved at surgery with potassium cardioplegia, is cytoprotective to myocytes. Indeed the electrochemical effects of opening the mitoKATP channel would seem to be very similar to that of potassium cardioplegia. This is of interest for the primary determinants of ATP resynthesis appear to be the primary determinants of the degree of H+(atp) channel openess. In other words the cytoprotection, or therapeutic dysfunction, induced in the heart by opening the mitoKATP channel with testosterone might be due to a fall in tissue pH and accompanying decline in energy charge and its inhibition of ATP-dependent enzyme activity in accordance with the Daniel Atkinson hypothesis (3). Might this be how testosterone increases the risk of developing acne?

  If so glibenclamide, a mitoKATP closer, and even pinacidil, a mitoKATP opener, might improve cutaneous tissue energetics and be effective treatments in patients with acne . Glibenclamide might increase the energy charge by increasing the rate of ATP resynthesis and pinacidil by decreasing the rate of ATP utilization. Pinacidil, the opener, might also make matters worse by increasing the dysfunction to a degree that precipitates harmful effects including apoptosis and even necrosis with its accompany inflammatory response. Glibenclamide would seem, therefore, the safer option. In opposing the action of testosterone glibenclamide might even be an ideal choice of drug to treat acne if indeed it is the product of a decline in pH and energy charge induced partially or wholly by testosterone and other androgens.

  Diabetics are at added risk of developing infections and glibenclamide is used to increase insulin release in insulin-dependent diabetics. It does so by closing the mitoKATP channel which induces an influx of Ca++ in beta cells which causes stored insulin to be released from its vesicles. Insulin release is normally triggered by a rise in ATP/ADP and, therefore, rise in pH and energy charge. In so doing it inhibits ATP resynthesis both be decreasing the availability of glucose and by inhibiting lipolysis and promoting the storage of fat in adipocytes. A rise in glucose also stimulates insulin secretion by causing an influx of Ca++ into beta cells. Thus a rise in fasting glucose, which is associated with adverse outcomes, might indeed be an indication of impaired tissue energetics (4). Diabetes is a disease characterised by impaired tissue energetics (5). That, rather than the elevated concetration of glucose in tissue fluids per se, is the most likely cause for the increased risk of infections in these patients.

  The easiest way to test the hypothesis that glibenclamide might be effective treatment for patients with acne would be to look at patients with acne who have been given the drug for insulin-dependent diabetes.

  References:

  1. Product of a tissue alkalosis induced by hypocarbia? Richard G Fiddian-Green CJA Online, 21 Dec 2004 re: T Tsubo, T Kudo, A Matsuki and T Oyama Decreased glucose utilization during prolonged anaesthesia and surgery Canadian Journal of Anesthesia, Vol 37, 645-649

  2. Fikret Er, MD*; Guido Michels, MD*; Natig Gassanov, MD; Francisco Rivero, MD; Uta C. Hoppe, MD Testosterone Induces Cytoprotection by Activating ATP-Sensitive K+ Channels in the Cardiac Mitochondrial Inner Membrane. Circulation. 2004;110:3100-3107

  3. Hardie DG, Hawley SA. AMP-activated protein kinase: the energy charge hypothesis revisited. Bioessays. 2001 Dec;23(12):1112-9.

  4. Richard G Fiddian-Green Hyperglycaemia = anaerobic threshold has been reached? http://www.heartjnl.com/cgi/eletters/89/5/512#634, 3 Mar 2005

  5. Richard G Fiddian-Green Grounds for abandoning "diabetes" as a diagnosis? http://www.postgradmedj.com/cgi/eletters/81/952/103#246, 3 Mar 2005

  Show Less

  Conflict of Interest:
  None declared.

  • Back to top