Sensory irritation to methylparaben is caused by its low metabolism in the skin
Rie Ninomiya
Safety Science Research Laboratories, Kao Corporation, Odawara, Japan
Search for more papers by this authorCorresponding Author
Takafumi Nishijima
Safety Science Research Laboratories, Kao Corporation, Odawara, Japan
Correspondence
Takafumi Nishijima, Safety Science Research Laboratories, Kao Corporation, Kotobuki-cho 5-3-28, Odawara, Kanagawa 250-0002, Japan.
Email: [email protected]
Search for more papers by this authorMasahiro Aoshima
Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
Search for more papers by this authorHitoshi Sakaguchi
Safety Science Research Laboratories, Kao Corporation, Odawara, Japan
Search for more papers by this authorYoshiki Tokura
Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
Allergic Disease Research Center and Department of Dermatology & Skin Oncology, Chutoen General Medical Center, Kakegawa, Japan
Search for more papers by this authorRie Ninomiya
Safety Science Research Laboratories, Kao Corporation, Odawara, Japan
Search for more papers by this authorCorresponding Author
Takafumi Nishijima
Safety Science Research Laboratories, Kao Corporation, Odawara, Japan
Correspondence
Takafumi Nishijima, Safety Science Research Laboratories, Kao Corporation, Kotobuki-cho 5-3-28, Odawara, Kanagawa 250-0002, Japan.
Email: [email protected]
Search for more papers by this authorMasahiro Aoshima
Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
Search for more papers by this authorHitoshi Sakaguchi
Safety Science Research Laboratories, Kao Corporation, Odawara, Japan
Search for more papers by this authorYoshiki Tokura
Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
Allergic Disease Research Center and Department of Dermatology & Skin Oncology, Chutoen General Medical Center, Kakegawa, Japan
Search for more papers by this authorAbstract
Sensitive skin is a well- known skin condition showing sensory irritation to daily used products such as cosmetics or pharmaceuticals, possibly containing sensory irritants. Methylparaben (MP), widely used as a preservative, is a representative sensory irritant and hydrolyzed in the skin. We aimed to clarify the relationship between MP sensory irritation and MP hydrolysis. First, we investigated the percutaneous penetration and hydrolysis of MP by using an ex vivo pig skin system and confirmed that topically applied MP was immediately hydrolyzed to p-hydroxybenzoic acid (PHBA). We next evaluated whether MP or PHBA causes sensory irritation using a well-used stinging test in human skin and found that MP, but not PHBA, induced irritation. Additionally, MP, but not PHBA, increased intracellular calcium in cultured TRPA1-expressed HEK293 cells, supporting the stimulatory activity of MP. Five and 10 individuals with sensitive and non-sensitive skin, respectively, were selected by a questionnaire and stinging test. In their biopsied skin samples, MP hydrolytic activity was significantly lower in sensitive than non-sensitive skin. Finally, we examined the activity of carboxylesterase (CES), which promptly hydrolyzes MP to PHBA. By using specific inhibitors of CES and CES2, we found that CES1 was responsible for MP metabolism. Our study suggests that low skin metabolism of topical agents is one of the causes of skin sensory irritation and resultant sensitive skin.
CONFLICT OF INTEREST STATEMENT
None declared.
REFERENCES
- 1Kligman AM, Sadiq I, Zhen IY. Crosby M, experimental studies on the nature of sensitive skin. Skin Res Technol. 2006; 12: 217–22.
- 2Willis CM, Shaw S, de Lacharrière O, Baverel M, Reiche L, Jourdain R, et al. Sensitive skin: an epidemiological study. Br J Dermatol. 2001; 145: 258–63.
- 3Richters R, Falcone D, Uzunbajakava N, Verkruysse W, van Erp P, van de Kerkhof P. What is sensitive skin? A systematic literature review of objective measurements. Skin Pharmacol Physiol. 2015; 28: 75–83.
- 4Kamide R, Misery L, Perez-Cullell N, Sibaud V, Taieb C. Sensitive skin evaluation in the Japanese population. J Dermatol. 2013; 40: 177–81.
- 5Misery L, Boussetta S, Nocera T, Perez-Cullell N, Taieb C. Sensitive skin in Europe. J Eur Acad Dermatol Venereol. 2009; 23: 376–81.
- 6Misery L, Jourdan E, Huet F, Brenaut E, Cadars B, Virassamynaïk S, et al. Sensitive skin in France: a study on prevalence, relationship with age and skin type and impact on quality of life. J Eur Acad Dermatol Venereol. 2018; 32: 791–5.
- 7Misery L, Sibaud V, Merial-Kieny C, Taieb C. Sensitive skin in the American population: prevalence, clinical data, and role of the dermatologist. Int J Dermatol. 2011; 50: 961–7.
- 8Pinto P, Rosado C, Parreirao C, Rodrigues LM. Is there any barrier impairment in sensitive skin? A quantitative analysis of sensitive skin by mathematical modeling of transepidermal water loss desorption curves. Skin Res Technol. 2011; 17: 181–5.
- 9Ohta M, Hikima R, Ogawa T. Physiological characteristics of sensitive skin classified by stinging test. J Jpn Cosmet Sci Soc. 2000; 23: 163–7.
- 10Roussaki-Schulze AV, Zafiriou E, Nikoulis D, Klimi E, Rallis E, Zintzaras E. Objective biophysical findings in patients with sensitive skin. Drugs Exp Clin Res. 2005; 31: 17–24.
- 11Raj N, Voegeli R, Rawlings AV, Doppler S, Imfeld D, Munday MR, et al. A fundamental investigation into aspects of the physiology and biochemistry of the stratum corneum in subjects with sensitive skin. Int J Cosmet Sci. 2017; 39: 2–10.
- 12Cho HJ, Chung BY, Lee HB, Kim HO, Park CW, Lee CH. Quantitative study of stratum corneum ceramides contents in patients with sensitive skin. J Dermatol. 2012; 39: 295–300.
- 13Kim SJ, Lim SU, Won YH, An SS, Lee EY, Moon SJ, et al. The perception threshold measurement can be a useful tool for evaluation of sensitive skin. Int J Cosmet Sci. 2008; 30: 333–7.
- 14Sun L, Wang X, Zhang Y, Wang T, Li X, Ma Y. The evaluation of neural and vascular hyper-reactivity for sensitive skin. Skin Res Technol. 2016; 22: 381–7.
- 15Buhé V, Vié K, Guéré C, Natalizio A, Lhéritier C, le Gall-Ianotto C, et al. Pathophysiological study of sensitive skin. Acta Derm Venereol. 2016; 96: 314–8.
- 16Ehnis-Perez A, Torres-Alvarez B, Cortes-Garcia D, Hernandez-Blanco D, Fuentes-Ahumada C, Castanedo-Cazares JP. Relationship between transient receptor potential vanilloid-1 expression and the intensity of sensitive skin symptoms. J Cosmet Dermatol. 2015; 15: 231–7.
- 17Fransway AF, Fransway PJ, Belsito DV, Yiannias JA. Paraben toxicology. Dermatitis. 2019; 30: 32–45.
- 18Fujii M, Okano Y, Masaki H. Skin sensory stimulation. J Soc Cosmet Chem Japan. 1989; 22: 229–35.
- 19Lee E, An S, Choi D, Moon S, Chang I. Comparison of objective and sensory skin irritations of several cosmetic preservatives. Contact Dermatitis. 2007; 56: 131–6.
- 20Fujita F, Moriyama T, Higashi T, Shima A, Tominaga M. Methyl p-hydroxybenzoate causes pain sensation through activation of TRPA1 channels. Br J Pharmacol. 2007; 151: 134–41.
- 21Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell. 2003; 112: 819–29.
- 22Baustista DM, Jordt SE, Nikai T, Tsuruda PR, Read AJ, Poblete J, et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell. 2006; 124: 1269–82.
- 23Kwan KY, Allchorne AJ, Vollrath MA, Christensen AP, Zhang DS, Woolf CJ, et al. TRPA1 contributes to cold mechanical and chemical nociception but is not essential for hair-cell transduction. Neuron. 2006; 50: 277–89.
- 24Jewell C, Bennett P, Mutch E, Ackermann C, Williams FM. Inter-individual variability in esterases in human liver. Biochem Pharmacol. 2007; 74: 932–9.
- 25Abbas S, Greige-Gerges H, Karam N, Piet MH, Netter P, Magdalou J. Metabolism of parabens (4-hydroxybenzoic acid esters) by hepatic esterases and UDP-glucuronosyltransferases in man. Drug Metab Pharmacokinet. 2010; 25: 568–77.
- 26Jewell C, Prusakiewicz JJ, Ackermann C, Payne NA, Fate G, Voorman R, et al. Hydrolysis of a series of parabens by skin microsomes and cytosol from human and minipigs and in whole skin in short-term culture. Toxicol Appl Pharmacol. 2007; 225: 221–8.
- 27Pazourekova S, Hojerova J, Klimova Z, Lucova M. Dermal absorption and hydrolysis of methylparaben in different vehicles through intact and damaged skin: using a pig-ear model in vitro. Food Chem Toxicol. 2013; 59: 754–65.
- 28Ishiwatari S, Suzuki T, Hitomi T, Yoshino T, Matsukuma S, Tsuji T. Effects of methyl paraben on skin keratinocytes. J Appl Toxicol. 2007; 27: 1–9.
- 29 OECD (Organisation for Economic Co-operation and Development). Test guideline 428. Skin absorption: In vitro method. 2004 Available from: https://ntp.niehs.nih.gov/iccvam/suppdocs/feddocs/oecd/oecdtg428-508.pdf
- 30Mugita N, Takahashi Y, Sakaguchi H, Nishiyama N. Development of a useful method for assessing sensory irritatancy of cosmetics. J Jpn Cosmet Sci Soc. 2012; 36: 7–12.
- 31Imai T, Takase Y, Iwase H, Hashimoto M. Involvement of carboxylesterase in hydrolysis of propranolol prodrug during permeation across rat skin. Pharmaceutics. 2013; 5: 371–84.
- 32Ozaki H, Sugihara K, Watanabe Y, Fujino C, Uramaru N, Sone T, et al. Comparative study of the hydrolytic metabolism of methyl-, ethyl-, propyl-, butyl-, heptyl- and dodecylparaben by microsomes of various rat and human tissues. Xinobiotica. 2013; 43: 1064–72.
- 33Sugibayashi K, Hayashi T, Morimoto Y. Simultaneous transport and metabolism of ethyl nicotinate in hairless rat skin after its topical application: the effect of enzyme distribution in skin. J Control Release. 1999; 62: 201–8.
- 34Tominaga M, Ozawa S, Tengara S, Ogawa H, Takamori K. Intraepidermal nerve fibers increase in dry skin of acetone-treated mice. J Dermatol Sci. 2007; 48: 103–11.
- 35Tominaga M, Tengara S, Kamo A, Ogawa H, Takamori K. Psoralen-ultraviolet a therapy alters epidermal Sema3A and NGF levels and modulates epidermal innervation in atopic dermatitis. J Dermatol Sci. 2009; 55: 40–6.
- 36Levin J, Maibach H. The correlation between transepidermal water loss and percutaneous absorption: an overview. J Control Release. 2005; 103: 291–9.
- 37Wang X, Shi J, Zhu HJ. Functional study of carboxylesterase 1 protein isoforms. Proteomics. 2019; 19:e1800288.
- 38Chen F, Zhang B, Parker RB, Laizure SC. Clinical implications of genetic variation in carboxylesterase drug metabolism. Expert Opin Drug Metab Toxicol. 2018; 14: 131–42.
- 39Yatagai T, Shimauchi T, Yamaguchi H, Sakabe JI, Aoshima M, Ikeya S, et al. Sensitive skin is highly frequent in extrinsic atopic dermatitis and correlates with disease severity markers but not necessarily with skin barrier impairment. J Dermatol Sci. 2018; 89: 33–9.
- 40Yokota T, Matsumoto M, Sakamaki T, Hikima R, Hayashi S, Yanagisawa M, et al. Classification of sensitive skin and development of a treatment system appropriate for each group. IFSCC Magazine. 2003; 6: 303–8.
