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Can Proton Pump Inhibitors Accentuate Skin Aging?
Archives of Medical Research 41 (2010) 147e148
OPINION
Can Proton Pump Inhibitors Accentuate Skin Aging? Mohammad Reza Namazia and Farideh Jowkarb a
Dermatology, Medicinal and Natural Products Chemistry Research Center and Dermatology Department, Shiraz, Iran b Dermatology, Shiraz University of Medical Sciences, Shiraz, Iran Received for publication November 10, 2009; accepted January 25, 2010 (ARCMED-D-09-00555).
Skin aging has long been important to human beings and in recent years this field has received tremendous attention by both researchers and the general population. Cutaneous aging includes two distinct phenomena, intrinsic aging and photoaging, and is characterized mainly by the loss of collagen fibers from dermis. Proton pump inhibitors (PPIs) are widely prescribed gastric acid-reducing agents that are usually consumed for long periods in some conditions such as gastroesophageal reflux disease. We suggest that PPIs can accentuate skin aging by two mechanisms. First, through increasing intralysosomal PH, PPIs can suppress transforming growth factorb (TGFb) processing and consequently decrease its secretion. Second, through inhibiting MNK, a P-type ATPase with steady-state localization at the trans-Golgi network, PPIs can hamper copper transport and consequently curb lysyl oxidase activity. Ó 2010 IMSS. Published by Elsevier Inc. Key Words: Proton pump inhibitors, Skin aging, Transforming growth factor b.
Cutaneous aging, being characterized mainly by the loss of collagen fibers, includes two distinct phenomena, i.e., intrinsic aging and photoaging. Intrinsic aging depends on time. The changes occur partially as the result of cumulative endogenous damage due to the continuous formation of reactive oxygen species (ROS), which are generated by oxidative cellular metabolism. Despite a strong antioxidant defense system, damage generated by ROS affects cellular constituents such as membranes, enzymes, and DNA. It has a genetic background, but is also due to decreased sex hormone levels. The telomere, a terminal portion of the eukaryotic chromosome, plays an important role. With each cell division, the length of the human telomere shortens. Even in fibroblasts of quiescent skin O30% of the telomere length is lost during adulthood (1). Extrinsic aging develops due to several factors: ionizing radiation, severe physical and psychological stress, alcohol intake, poor nutrition, overeating, environmental pollution, and exposure to UV radiation. Among all these environmental factors, UV radiation contributes up to 80% (1).
Address reprint requests to: Jowkar Farideh, Shiraz University, Zand Street, Shiraz, Iran, Islamic Republic of; Phone: þ987112319049; FAX: þ987112319049.; E-mail: [email protected]
UV irradiation activates cell surface receptors, including receptors for epidermal growth factor to induce signaling culminating in activation of the nuclear transcription complex AP-1. Increased AP-1 activity interferes with synthesis of the major dermal collagens I and III by blocking the effect of transforming growth factor beta (TGFb). AP-1 also decreases the level of TGFb receptors, further inhibiting collagen transcription (2). TGFb plays a pivotal role in the production of collagen. TGFb-treated fibroblasts display enhanced production of collagen and other extracellular matrix molecules. In addition, TGFb inhibits the production of metalloproteinases by fibroblasts and stimulates the production of inhibitors of the same metalloproteinases (3). Proton pump inhibitors can interfere with TGFb production. TGFb is synthesized as a precursor protein, pro-TGFb, that must be cleaved by a furin-like proteinase before it becomes biologically active. Alkalinization of the transGolgi network (TGN)/endosome system suppresses TGFb processing and decreases TGFb secretion. The alkalinizing lysosomotropic drugs chloroquine, hydroxychloroquine, amodiaquine, and azithromycin had a negative effect on the overall production of mature bioactive TGFb. Mice treated with chloroquine showed a decrease in bronchoalveolar lavage fluid TGFb (4).
0188-4409/$esee front matter. Copyright Ó 2010 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2010.02.006
148
Namazi and Jowkar/ Archives of Medical Research 41 (2010) 147e148
Vacuolar proton pump (V-ATPase) is expressed in eukaryotes from yeast to man. It is present not only in the membrane of organelles but also in the plasma membrane. The V-ATPase pumps protons from the cytoplasm to the lumen of vacuoles or into the extracellular space using the energy produced by ATP hydrolysis (5). PPIs are substituted benzimidazole derivatives and membrane-permeable, weak bases that accumulate in acid spaces of the active parietal cell as prodrugs. Here they undergo acid-catalyzed conversion to the active derivatives which inhibit Hþ/KþATPase, a V-ATPase, thus inhibiting acid secretion up to 36 h (6). Five PPIs are currently available for clinical use: omeprazole and its S-isomer, esomeprazole, lansoprazole, rabeprazole and pantoprazole (7). Importantly, PPIs can decrease the acidity of lysosomes and exert the following interesting related effects: a) treatment with PPIs induces sensitization of cancer cells to chemotherapeutics via modifications of cellular pH gradients (8). Recently, ionizing radiation has been reported to induce development of acidic vesicular organelles in neoplastic epithelial cells. Interference with acidification of vesicular organelles by bafilomycin A1 results in increased radiosensitivity (7). Inhibitors of V-ATPase, including PPIs, are suggested to produce a supra-additive effect with other anticancer agents or irradiation (9). b) Omeprazole has been shown to exert in vitro antimalarial and, more importantly, in vivo anti-leishmanial (10) activities because of the blockade of V-ATPase on parasitic acid food vacuoles and parasitecontaining phagolysosomes of human macrophages, respectively. c) Lansoprazole may modulate rhinoviral airway inflammation by its hindering of lysosomal acidification as the entry of RNA of a major rhinovirus, type 14 rhinovirus, into the cytoplasm of infected cells is suggested to be mediated by the destabilization from receptor binding and by endosomal acidification (7). As an intralysosomal acidic pH is required for conversion of pro-TGFb to TGFb by proteinases, alkalization of lysosomal pH by PPIs can hamper TGFb production.
PPIs May Interfere with Collagen Cross-linking Stabilization of newly formed, collagen fibrils occurs initially through the formation of difunctional, lysyl oxidase-mediated cross-links whereby lysine or hydroxylysine residues in the nonhelical portions of the molecule (telopeptides) are converted into aldehydes, which then condense with hydroxylysine and other residues in neighboring molecules to form intermolecular bonds (11). Lysyl oxidase is a major copper-dependent enzyme. When its activity decreases, collagen cross-links become defective (12).
Copper is a trace element whose intracellular level must be carefully controlled presumably by regulated transport mechanism. P-type ATPases are involved in ATPdependent transport of cations across membrane in both prokaryocyte and eukaryocyte (13). PPIs can block MNK, a P-type ATPase, which has steady-state localization at the trans-Golgi network and transports copper (14). Therefore, by interfering with this pathway, PPIs can interfere with collagen synthesis and further contribute to skin aging. In conclusion, PPIs, by increasing intralysosomal pH and hampering copper transport, can interfere with both collagen production and its cross-linking, hence accelerating skin aging process. Our commentary justifies research on the influence of PPIs on skin aging.
References 1. Puizina-Ivic´ N. Skin aging. Acta Dermatovenerol Alp Panonica Adriat 2008;17:47e54. 2. Fisher GJ, Kang S, Varani J, et al. Mechanism of photoaging and chronological skin aging. Arch Dermatol 2002;138:1462e1470. 3. Williams IR, Rich BE, Kupper TS. Cytokines. In: Wolff K, Goldsmith LA, eds. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York: McGraw Hill;2008. p. 126. 4. Basque J, Martel M, Leduc R, et al. Lysosomotropic drugs inhibit maturation of transforming growth factor-beta. Can J Physiol Pharmacol 2008;86:606e612. 5. Nishi T, Forgac M. The vacuolar (Hþ)-ATPases—nature’s most versatile proton pumps. Nat Rev Mol Cell Biol 2002;3:94e103. 6. Shi S, Klotz U. Proton pump inhibitors: an update of their clinical use and pharmacokinetics. Eur J Clin Pharmacol 2008;64:935e951. 7. Namazi MR, Sharifian M. The potential anti-xanthoma and antiatherosclerotic effects of proton pump inhibitors. J Clin Pharm Ther 2008;33:579e580. 8. De Milito A, Iessi E, Logozzi M, et al. Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species. Cancer Res 2007;67: 5408e5417. 9. Long X, Crow MT, Sollott SJ, et al. Enhanced expression of p53 and apoptosis induced by blockade of the vacuolar proton ATPase in cardiomyocytes. J Clin Invest 1998;101:1453e1461. 10. Namazi MR, Jowkar F. A succinct review of the general and immunological pharmacologic effects of proton pump inhibitors. J Clin Pharm Ther 2008;33:215e217. 11. Robins SP. Biochemistry and functional significance of collagen crosslinking. Biochem Soc Trans 2007;35:849e852. 12. Byers PH, Siegel RC, Holbrook KA, et al. X-linked cutis laxa: defective cross-link formation in collagen due to decreased lysyl oxidase activity. N Engl J Med 1980;303:61e65. 13. Petris MJ, Mercer JF, Culvenor JG, et al. Ligand-regulated transport of the Menkes copper P-type ATPase efflux pump from the Golgi apparatus to the plasma membrane: a novel mechanism of regulated trafficking. EMBO J 1996;15:6084e6095. 14. Namazi MR. Proton pump inhibitors may trigger vitiligo by rendering melanocytes prone to apoptosis. Br J Dermatol 2007;156: 1371e1373.
OPINION
Can Proton Pump Inhibitors Accentuate Skin Aging? Mohammad Reza Namazia and Farideh Jowkarb a
Dermatology, Medicinal and Natural Products Chemistry Research Center and Dermatology Department, Shiraz, Iran b Dermatology, Shiraz University of Medical Sciences, Shiraz, Iran Received for publication November 10, 2009; accepted January 25, 2010 (ARCMED-D-09-00555).
Skin aging has long been important to human beings and in recent years this field has received tremendous attention by both researchers and the general population. Cutaneous aging includes two distinct phenomena, intrinsic aging and photoaging, and is characterized mainly by the loss of collagen fibers from dermis. Proton pump inhibitors (PPIs) are widely prescribed gastric acid-reducing agents that are usually consumed for long periods in some conditions such as gastroesophageal reflux disease. We suggest that PPIs can accentuate skin aging by two mechanisms. First, through increasing intralysosomal PH, PPIs can suppress transforming growth factorb (TGFb) processing and consequently decrease its secretion. Second, through inhibiting MNK, a P-type ATPase with steady-state localization at the trans-Golgi network, PPIs can hamper copper transport and consequently curb lysyl oxidase activity. Ó 2010 IMSS. Published by Elsevier Inc. Key Words: Proton pump inhibitors, Skin aging, Transforming growth factor b.
Cutaneous aging, being characterized mainly by the loss of collagen fibers, includes two distinct phenomena, i.e., intrinsic aging and photoaging. Intrinsic aging depends on time. The changes occur partially as the result of cumulative endogenous damage due to the continuous formation of reactive oxygen species (ROS), which are generated by oxidative cellular metabolism. Despite a strong antioxidant defense system, damage generated by ROS affects cellular constituents such as membranes, enzymes, and DNA. It has a genetic background, but is also due to decreased sex hormone levels. The telomere, a terminal portion of the eukaryotic chromosome, plays an important role. With each cell division, the length of the human telomere shortens. Even in fibroblasts of quiescent skin O30% of the telomere length is lost during adulthood (1). Extrinsic aging develops due to several factors: ionizing radiation, severe physical and psychological stress, alcohol intake, poor nutrition, overeating, environmental pollution, and exposure to UV radiation. Among all these environmental factors, UV radiation contributes up to 80% (1).
Address reprint requests to: Jowkar Farideh, Shiraz University, Zand Street, Shiraz, Iran, Islamic Republic of; Phone: þ987112319049; FAX: þ987112319049.; E-mail: [email protected]
UV irradiation activates cell surface receptors, including receptors for epidermal growth factor to induce signaling culminating in activation of the nuclear transcription complex AP-1. Increased AP-1 activity interferes with synthesis of the major dermal collagens I and III by blocking the effect of transforming growth factor beta (TGFb). AP-1 also decreases the level of TGFb receptors, further inhibiting collagen transcription (2). TGFb plays a pivotal role in the production of collagen. TGFb-treated fibroblasts display enhanced production of collagen and other extracellular matrix molecules. In addition, TGFb inhibits the production of metalloproteinases by fibroblasts and stimulates the production of inhibitors of the same metalloproteinases (3). Proton pump inhibitors can interfere with TGFb production. TGFb is synthesized as a precursor protein, pro-TGFb, that must be cleaved by a furin-like proteinase before it becomes biologically active. Alkalinization of the transGolgi network (TGN)/endosome system suppresses TGFb processing and decreases TGFb secretion. The alkalinizing lysosomotropic drugs chloroquine, hydroxychloroquine, amodiaquine, and azithromycin had a negative effect on the overall production of mature bioactive TGFb. Mice treated with chloroquine showed a decrease in bronchoalveolar lavage fluid TGFb (4).
0188-4409/$esee front matter. Copyright Ó 2010 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2010.02.006
148
Namazi and Jowkar/ Archives of Medical Research 41 (2010) 147e148
Vacuolar proton pump (V-ATPase) is expressed in eukaryotes from yeast to man. It is present not only in the membrane of organelles but also in the plasma membrane. The V-ATPase pumps protons from the cytoplasm to the lumen of vacuoles or into the extracellular space using the energy produced by ATP hydrolysis (5). PPIs are substituted benzimidazole derivatives and membrane-permeable, weak bases that accumulate in acid spaces of the active parietal cell as prodrugs. Here they undergo acid-catalyzed conversion to the active derivatives which inhibit Hþ/KþATPase, a V-ATPase, thus inhibiting acid secretion up to 36 h (6). Five PPIs are currently available for clinical use: omeprazole and its S-isomer, esomeprazole, lansoprazole, rabeprazole and pantoprazole (7). Importantly, PPIs can decrease the acidity of lysosomes and exert the following interesting related effects: a) treatment with PPIs induces sensitization of cancer cells to chemotherapeutics via modifications of cellular pH gradients (8). Recently, ionizing radiation has been reported to induce development of acidic vesicular organelles in neoplastic epithelial cells. Interference with acidification of vesicular organelles by bafilomycin A1 results in increased radiosensitivity (7). Inhibitors of V-ATPase, including PPIs, are suggested to produce a supra-additive effect with other anticancer agents or irradiation (9). b) Omeprazole has been shown to exert in vitro antimalarial and, more importantly, in vivo anti-leishmanial (10) activities because of the blockade of V-ATPase on parasitic acid food vacuoles and parasitecontaining phagolysosomes of human macrophages, respectively. c) Lansoprazole may modulate rhinoviral airway inflammation by its hindering of lysosomal acidification as the entry of RNA of a major rhinovirus, type 14 rhinovirus, into the cytoplasm of infected cells is suggested to be mediated by the destabilization from receptor binding and by endosomal acidification (7). As an intralysosomal acidic pH is required for conversion of pro-TGFb to TGFb by proteinases, alkalization of lysosomal pH by PPIs can hamper TGFb production.
PPIs May Interfere with Collagen Cross-linking Stabilization of newly formed, collagen fibrils occurs initially through the formation of difunctional, lysyl oxidase-mediated cross-links whereby lysine or hydroxylysine residues in the nonhelical portions of the molecule (telopeptides) are converted into aldehydes, which then condense with hydroxylysine and other residues in neighboring molecules to form intermolecular bonds (11). Lysyl oxidase is a major copper-dependent enzyme. When its activity decreases, collagen cross-links become defective (12).
Copper is a trace element whose intracellular level must be carefully controlled presumably by regulated transport mechanism. P-type ATPases are involved in ATPdependent transport of cations across membrane in both prokaryocyte and eukaryocyte (13). PPIs can block MNK, a P-type ATPase, which has steady-state localization at the trans-Golgi network and transports copper (14). Therefore, by interfering with this pathway, PPIs can interfere with collagen synthesis and further contribute to skin aging. In conclusion, PPIs, by increasing intralysosomal pH and hampering copper transport, can interfere with both collagen production and its cross-linking, hence accelerating skin aging process. Our commentary justifies research on the influence of PPIs on skin aging.
References 1. Puizina-Ivic´ N. Skin aging. Acta Dermatovenerol Alp Panonica Adriat 2008;17:47e54. 2. Fisher GJ, Kang S, Varani J, et al. Mechanism of photoaging and chronological skin aging. Arch Dermatol 2002;138:1462e1470. 3. Williams IR, Rich BE, Kupper TS. Cytokines. In: Wolff K, Goldsmith LA, eds. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York: McGraw Hill;2008. p. 126. 4. Basque J, Martel M, Leduc R, et al. Lysosomotropic drugs inhibit maturation of transforming growth factor-beta. Can J Physiol Pharmacol 2008;86:606e612. 5. Nishi T, Forgac M. The vacuolar (Hþ)-ATPases—nature’s most versatile proton pumps. Nat Rev Mol Cell Biol 2002;3:94e103. 6. Shi S, Klotz U. Proton pump inhibitors: an update of their clinical use and pharmacokinetics. Eur J Clin Pharmacol 2008;64:935e951. 7. Namazi MR, Sharifian M. The potential anti-xanthoma and antiatherosclerotic effects of proton pump inhibitors. J Clin Pharm Ther 2008;33:579e580. 8. De Milito A, Iessi E, Logozzi M, et al. Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species. Cancer Res 2007;67: 5408e5417. 9. Long X, Crow MT, Sollott SJ, et al. Enhanced expression of p53 and apoptosis induced by blockade of the vacuolar proton ATPase in cardiomyocytes. J Clin Invest 1998;101:1453e1461. 10. Namazi MR, Jowkar F. A succinct review of the general and immunological pharmacologic effects of proton pump inhibitors. J Clin Pharm Ther 2008;33:215e217. 11. Robins SP. Biochemistry and functional significance of collagen crosslinking. Biochem Soc Trans 2007;35:849e852. 12. Byers PH, Siegel RC, Holbrook KA, et al. X-linked cutis laxa: defective cross-link formation in collagen due to decreased lysyl oxidase activity. N Engl J Med 1980;303:61e65. 13. Petris MJ, Mercer JF, Culvenor JG, et al. Ligand-regulated transport of the Menkes copper P-type ATPase efflux pump from the Golgi apparatus to the plasma membrane: a novel mechanism of regulated trafficking. EMBO J 1996;15:6084e6095. 14. Namazi MR. Proton pump inhibitors may trigger vitiligo by rendering melanocytes prone to apoptosis. Br J Dermatol 2007;156: 1371e1373.