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Proton Pump Inhibitors Decrease Melanogenesis in Melanocytes

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Proton Pump Inhibitors Decrease Melanogenesis in Melanocytes 726 BIOMEDICAL REPORTS 3: 726-730, 2015 Proton pump inhibitors decrease melanogenesis in melanocytes SEUNG-HWA BAEK1 and SANG-HAN LEE1,2 Departments of 1Food Science and Biotechnology and 2Nano-Science and Technology, Kyungpook National University, Daegu 702-701, Republic of Korea Received April 27, 2015; Accepted June 10, 2015 DOI: 10.3892/br.2015.492 Abstract. Proton pump inhibitors (PPIs) are widely used as the cells that line the stomach, regarding the reduction of acid inhibitors of gastric juice secretion for treatment of gastro- production, which is relatively well-understood (2). Recently, esophageal reflux disease. However, there are no previous however, it was reported that treatment with PPIs could worsen studies of the effects on melanogenesis resulting from PPI the symptoms of vitiligo in patients suffering from this skin treatments. Therefore, the aim of the present study was to inves- pigmentation disorder (3). In one study, the investigators tigate the effects of PPIs on melanogenesis in melan-a cells demonstrated that PPI treatment could lead to increased derived from immortalized mouse melanocytes. Tyrosinase destruction of melanocytes in vitiligo patients via the induc- activity and copper-chelating activity were measured spec- tion of apoptosis (4). Furthermore, one African-American trophotometrically. In addition, the melanin content and patient receiving PPIs proceeded to widespread vitiligo at the viability of melan-a cells treated with PPIs were assessed and same time as when the daily use of a PPI, 40 mg esomeprazole, the mRNA levels of melanogenesis-associated genes were began during the 3 years. Following the termination of esome- measured by reverse transcription-polymerase chain reaction. prazole intake, these patients were able to initiate an extremely Treatment with rabeprazole, but not the other PPIs tested, slow repigmentation (5). The effects of PPIs on melanogenesis, resulted in strong, dose-dependent inhibition of mushroom however, have rarely been recognized. tyrosinase (TYR). By contrast, each of the PPIs tested exhib- Melanogenensis is a complex process involving numerous ited copper-chelating activity. Treatment of melan-a cells with different metabolic signals and a series of enzymes. In 100 µM concentrations of the PPIs resulted in significantly human melanocytes, the melanin pigment is derived from reduced melanin synthesis and reduced expression of several hydroxylation of L-tyrosine to L-3,4-dihydroxyphenylalanine melanogenesis-associated genes, including TYR, TYR-related (L-DOPA) by tyrosinase (TYR) (EC 1.14.18.1) with two protein-1 (TRP‑1) and TRP‑2, and microphthalmia-associated copper ions at the active center (6). Overexpression of the transcription factor, but did not result in cytotoxic effects. genes involved in pigment formation was shown to result in These results suggest that PPIs inhibit melanin biosynthesis in pigmentation disorders, including lentigo senilis and urticaria melan-a cells via the downregulation of melanogenesis-asso- pigmentosa, as well as in skin discoloration issues, such as ciated genes. Furthermore, the findings indicate that PPIs in melasma, freckles and chloasma. Thus, TYR is a primary general could be utilized as skin-whitening agents and/or as target of screens designed to identify depigmentation agents. biomaterial for treating hyperpigmentation disorders. In addition to its role in pigmentation disorders, TYR has been revealed to have a role in Parkinson's disease (7) and other Introduction neurodegenerative diseases (8). Therefore, the development of anti-melanogenic agents is an important goal for the cosmetic Proton pump inhibitors (PPIs) are commonly used to treat acid and medicinal industry (9). Melanin biosynthesis is modulated reflux disease and ulcers of the stomach and the duodenum. by the expression of microphthalmia-associated transcription These compounds include omeprazole, rabeprazole, esomepra- factor (MITF), which regulates the transcriptional expression zole, lansoprazole and pantoprazole, which are available under of the TYR, TYR-related protein-1 (TRP‑1) and TRP‑2 genes a variety of brand names (1). Multiple studies have examined in melanocytes (10). A previous study demonstrated that omeprazole treatment significantly reduced melanogenesis by inhibiting ATP7A gene expression and by enhancing degradation of TYR (11); however, the anti-melanogenic effects of other PPIs are yet to Correspondence to: Dr Sang-Han Lee, Department of Food Science and Biotechnology, Kyungpook National University, be examined. The objective of the present study was to assess 80 Dahak-ro, Daegu 702-701, Republic of Korea the effects of PPIs on melanogenesis in melanocytes. E-mail: [email protected] Materials and methods Key words: proton pump inhibitors, tyrosinase, anti-melanogenic effects, melanogenesis-associated genes, melanocyte Materials. Arbutin, L-DOPA, L-tyrosine, N-phenylthiourea (PTU), 12-O-tetradecanoylphorbol-13-acetate (TPA), TYR, sodium hydroxide (NaOH), thiazolyl blue tetrazolium bromide BAEK and LEE: DECREASE OF MELANOGENESIS BY PROTON PUMP INHIBITORS 727 (MTT), dimethyl sulfoxide (DMSO), rabeprazole, esome- MTT solution, 1 ml of DMSO was added to each well with prazole, lansoprazole and pantoprazole were obtained from vigorous mixing. The absorbance of each well at 470 nm was Sigma-Aldrich (St. Louis, MO, USA). All other reagents and determined using a microplate reader (PerkinElmer). chemicals were of high-grade and are commercially available. Melanization inhibition assay using melan‑a cells. Cells were Measurement of mushroom TYR activity. TYR activity was seeded in 24-well plates (BD Biosciences, Franklin Lakes, NJ, measured as described previously (6). The mushroom TYR USA) at a density of 1x105 cells/well and allowed to attach (EC 1.14.18.1) reactions were performed in 96-well micro- overnight. The supernatants were subsequently removed and plates (SPL Life Sciences Co., Ltd., Pocheon, Gyeonggi, replaced with fresh media containing various concentrations Korea) and consisted of 150 µl of 0.1 M phosphate buffer (25, 50, 100 and 200 µM) of the test compounds. Cells were (pH 6.5), 3 µl of test sample, 36 µl of 1.5 mM L-tyrosine and cultured for 72 h and further incubated for 1 day. Following 7 µl of mushroom TYR [2,100 U/ml in 0.05 M phosphate washing with PBS, the cells were lysed with 250 µl of 1 N buffer, (pH 6.5)]. The initial absorbance of each mixture NaOH and transferred to 96-well plates. The melanin content and the absorbance after incubation at 37˚C for 30 min, was was estimated by measuring the absorbance at 405 nm using a measured at 490 nm using a microplate reader (PerkinElmer, microplate reader (PerkinElmer). Arbutin was used as a posi- Waltham, MA, USA). The inhibitory activity was subsequently tive control (10). calculated using the following formula: Inhibitory activity (%) = [(A - B) - (C - D)]/(A - B) x 100; where A refers to the Reverse transcription‑polymerase chain reaction (RT‑PCR) absorbance of the control sample following the reaction, B is analysis of mRNA expression. Total RNA was extracted the absorbance of the control sample prior to the reaction, C is from melan-a cells using TRIzol reagent (Invitrogen Life the absorbance of the treated sample following the reaction Technologies, Waltham, MA, USA), according to the manufac- and D is the absorbance of the treated sample prior to the reac- turer's instructions, with slight modification (14). Total RNA tion. (2 µg) was reverse transcribed with RT (MP Biomedicals, Santa Ana, CA, USA) and oligo (dT) primers. cDNA was Measurement of copper‑chelating activity. The amplified using a PCR Thermal Cycler Dice TP600 (Takara copper-chelating activity was determined using the pyrocat- Bio, Inc., Shiga, Japan) and oligonucleotide primers specific echol violet (PV) method as described previously, and with for mouse transcripts (6). The resulting PCR products were slight modifications (12). Samples were mixed with 1 ml of visualized by ethidium bromide staining following agarose gel 50 mM sodium acetate buffer (pH 6.0) and 100 µl of 2 mM electrophoresis. CuSO4. After 10 min of incubation at room temperature, 100 µl of 2 mM PV was added. Solutions were incubated Statistical analysis. Data are expressed as the means ± stan- for 20 min at room temperature and the absorbance of each dard deviation. Statistical significance was determined by the sample at 632 nm (A632) was measured. DMSO and PTU were Student's t-test for independent means using Microsoft Excel used as a negative control and as a standard metal chelator, software (Microsoft Corporation, Redmond, WA, USA). P<0.05 respectively. The copper‑chelating activity was calculated was considered to indicate a statistically significant difference. using the following formula: Copper-chelating activity (%) = [1 - (A - B)/(C - D)] x 100; where A is the A632 of the Results sample + buffer + CuSO4 + PV mixture, B is the A632 of the sample + buffer + buffer + PV mixture, C is the A632 nm of the Effect of PPIs on TYR and copper‑chelating activity. The buffer + buffer + CuSO4 + PV mixture and D is the A632 nm of effect of PPIs on the activity of TYR, a crucial enzyme for the buffer + buffer + buffer + PV mixture. melanin synthesis, was examined. As depicted in Fig. 1, rabeprazole treatment resulted in significant, dose‑dependent Cell cultures. The melan-a immortalized mouse melanocyte inhibition of TYR activity and the 50% inhibitory concentra- cell line, which was derived from B57BL6 mice (13), was tion (IC50) of this compound was 110.1 µM. The IC50 of the purchased from Bennett et al (13) (St. George's University of arbutin positive control was ~212.3 µM (Fig. 1A). By contrast, London, London, UK). The cells were cultured in RPMI-1640 the PPIs esomeprazole, lansoprazole and pantoprazole exerted medium (HyClone, Logan, UT, USA) supplemented with no inhibitory effect on TYR activity. 10% fetal bovine serum (HyClone), streptomycin-penicillin To understand the role of metal chelation in PPI TYR (100 µg/ml each; HyClone) and 200 nM TPA (a potent tumor inhibition, the copper-chelating activities of each PPI were promoter) at 37˚C in 5% CO2.
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