title: Hydrolytic metabolism of phenyl and benzyl salicylates, fragrances and flavoring agents in foods, by microsomes of rat and human tissues.
abstract: Salicylates are used as fragrance and flavor ingredients for foods, as UV absorbers and as medicines. Here, we examined the hydrolytic metabolism of phenyl and benzyl salicylates by various tissue microsomes and plasma of rats, and by human liver and small-intestinal microsomes. Both salicylates were readily hydrolyzed by tissue microsomes, predominantly in small intestine, followed by liver, although phenyl salicylate was much more rapidly hydrolyzed than benzyl salicylate. The liver and small-intestinal microsomal hydrolase activities were completely inhibited by bis(4-nitrophenyl)phosphate, and could be extracted with Triton X-100. Phenyl salicylate-hydrolyzing activity was co-eluted with carboxylesterase activity by anion exchange column chromatography of the Triton X-100 extracts of liver and small-intestinal microsomes. Expression of rat liver and small-intestinal isoforms of carboxylesterase, Ces1e and Ces2c (AB010632), in COS cells resulted in significant phenyl salicylate-hydrolyzing activities with the same specific activities as those of liver and small-intestinal microsomes, respectively. Human small-intestinal microsomes also exhibited higher hydrolyzing activity than liver microsomes towards these salicylates. Human CES1 and CES2 isozymes expressed in COS cells both readily hydrolyzed phenyl salicylate, but the activity of CES2 was higher than that of CES1. These results indicate that significant amounts of salicylic acid might be formed by microsomal hydrolysis of phenyl and benzyl salicylates in vivo. The possible pharmacological and toxicological effects of salicylic acid released from salicylates present in commercial products should be considered.
authors: Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan.
authors: Hitomi
authors: H
authors: Ozaki
authors: Faculty of Pharmaceutical Science, Hiroshima International University, Koshingai 5-1-1, Kure, Hiroshima 737-0112, Japan.
authors: Kazumi
authors: K
authors: Sugihara
authors: Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan.
authors: Yuki
authors: Y
authors: Tamura
authors: Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan.
authors: Chieri
authors: C
authors: Fujino
authors: Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan.
authors: Yoko
authors: Y
authors: Watanabe
authors: Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan.
authors: Naoto
authors: N
authors: Uramaru
authors: Faculty of Pharmaceutical Sciences, Setsunan University, Nagaotoge-cho 45-1, Hirakata, Osaka 573-0101, Japan.
authors: Tomomichi
authors: T
authors: Sone
authors: Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan.
authors: Shigeru
authors: S
authors: Ohta
authors: Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan. Electronic address: kitamura@nichiyaku.ac.jp.
authors: Shigeyuki
authors: S
authors: Kitamura
mesh_terms: D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism; D005421:Flavoring Agents / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012459:Salicylates / Q000737:chemistry / Q000378:metabolism*
chemical_list: D005421:Flavoring Agents; D012459:Salicylates; C026041:phenyl salicylate; D002265:Carboxylic Ester Hydrolases; C039672:benzyl salicylate
keywords: Carboxylesterase; Human liver and small-intestinal microsomes; Hydrolytic metabolism; Rat tissue microsomes; Salicylate; Salicylic acid