Sklyarova Yulia, Fomenko Iryna, Lozynska Iryna, Lozynskyi Andrii, Lesyk Roman, Sklyarov Alexandr
Department of Biochemistry, Danylo Halytsky Lviv National Medical University, Lviv 79010, Ukraine.
Department of Pharmaceutical, Organic and Bioorganic Chemistry of Danylo Halytsky Lviv National Medical University, Lviv 79010, Ukraine.
Sci Pharm. 2017 Oct 24;85(4):35. doi: 10.3390/scipharm85040035.
Small intestinal injury is known to be one of the most commonly appearing pathologies, resulting in the use of medications such as: nonsteroidal anti-inflammatory drugs (NSAIDs), antitumor drugs and angiotensin-converting enzyme (ACE) inhibitors. The principal objective of this study is to evaluate the action of a novel mercaptoacrylic acid derivative able to release H₂S on parameters of NO-synthase system and oxidative stress. Inducing enteropathy, three types of medications were used: indomethacin, an NSAID (35 mg/kg); methotrexate, an antitumor drug (10 mg/kg); and enalapril, an ACE inhibitor (2 mg/kg/day). 2-[(4-chlorophenyl-carbamoyl)-methyl]-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-acrylic acid (2C3DHTA) was introduced based on the background of medication-induced enteropathy (10 mg/kg/day). The survey showed that malondialdehyde (MDA) concentration, myeloperoxidase (MPO) activity, superoxide dismutase (SOD), catalase, and NO-synthases (NOS) were determined in the small intestinal mucosa. The increase in inducible NO-synthase (iNOS) activity was due to indomethacin and methotrexate administration. Constitutive NO-synthase (cNOS) activity was decreased by an ACE-inhibitor. The cytoprotective effect was demonstrated by 2C3DHTA, which returned iNOS activity to its control level and increased cNOS activity. The enterotoxic action of studied medication was accompanied by the development of oxidative stress manifested, activity of MPO was increased. MPO activity and manifestations of oxidative stress were decreased by 2C3DHTA. Effects of 2C3DHTA can be explained by the action of H₂S, released from this compound in the gastrointestinal (GI) system.
小肠损伤是最常见的病理状况之一，会导致使用诸如非甾体抗炎药（NSAIDs）、抗肿瘤药物和血管紧张素转换酶（ACE）抑制剂等药物。本研究的主要目的是评估一种能够释放H₂S的新型巯基丙烯酸衍生物对一氧化氮合酶系统参数和氧化应激的作用。通过使用三种药物诱导肠病：消炎痛，一种NSAID（35毫克/千克）；甲氨蝶呤，一种抗肿瘤药物（10毫克/千克）；以及依那普利，一种ACE抑制剂（2毫克/千克/天）。在药物诱导的肠病背景下引入2-[(4-氯苯基-氨基甲酰基)-甲基]-3-(3,5-二叔丁基-4-羟基苯基)-丙烯酸（2C3DHTA）（10毫克/千克/天）。调查显示，在小肠黏膜中测定了丙二醛（MDA）浓度、髓过氧化物酶（MPO）活性、超氧化物歧化酶（SOD）、过氧化氢酶和一氧化氮合酶（NOS）。诱导型一氧化氮合酶（iNOS）活性的增加是由于消炎痛和甲氨蝶呤的给药。组成型一氧化氮合酶（cNOS）活性因ACE抑制剂而降低。2C3DHTA表现出细胞保护作用，它使iNOS活性恢复到对照水平并增加了cNOS活性。所研究药物的肠毒性作用伴随着氧化应激的发展，表现为MPO活性增加。2C3DHTA降低了MPO活性和氧化应激的表现。2C3DHTA的作用可以通过该化合物在胃肠道（GI）系统中释放的H₂S的作用来解释。
