Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
Department of Physiology and Pharmacology, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Physiology-Pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
Biomed Pharmacother. 2018 Jan;97:233-239. doi: 10.1016/j.biopha.2017.10.113. Epub 2017 Nov 6.
Hepatotoxicity is one of the major side effects of methotrexate (MTX), which restricts the clinical use of this drug. Berberine (BBR) is a natural compound with multiple pharmacological activities such as antioxidant, antiapoptotic and anti-inflammatory effects. In this study, the effect of BBR on MTX-induced hepatotoxicity was studied. A total number of 28 male Wistar rats were randomly divided into four experimental groups. Rats were pretreated with BBR orally with dose of 100mg/kg for 10 consecutive days and MTX (20mg/kg, intraperitoneally) was administrated on the 9th day. Then on day 11, blood samples were collected to determine serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). The extracted livers were used for histological examination, biochemical assays and real time PCR studies. Malondialdehyde (MDA), glutathione (GSH), protein carbonyl (PC), nitric oxide (NO) levels, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and myeloperoxidase (MPO) activities were assessed in hepatic tissue. In addition, the expression of SOD and PGx was measured using real-time PCR method in hepatic tissue. Results showed that MTX administration significantly increases AST, ALT and ALP levels (all p<0.001). It also, increases MDA, PC, NO levels and MPO activity (p<0.001, p<0.01, p<0.05 and p<0.01 respectively). Moreover, MTX decreases hepatic GSH level, SOD, GPx and CAT activities (all p<0.001). Pre-treatment with BBR for 10days prevented some of these changes. Serum levels of AST and ALT decreased (all p<0.001). Hepatic MDA level decreased (p<0.001) and GSH level as well as GPx activity increased (p<0.05 and p<0.01 respectively). Our results indicated that BBR might be useful for prevention of the hepatotoxicity induced by MTX via ameliorative effects on biochemical and oxidative stress indices.
肝毒性是甲氨蝶呤（MTX）的主要副作用之一，这限制了该药物的临床应用。小檗碱（BBR）是一种具有多种药理活性的天然化合物，如抗氧化、抗凋亡和抗炎作用。在这项研究中，研究了 BBR 对 MTX 诱导的肝毒性的影响。将 28 只雄性 Wistar 大鼠随机分为四组实验。大鼠连续 10 天每天口服 BBR（100mg/kg）预处理，第 9 天腹腔注射 MTX（20mg/kg）。然后在第 11 天，采集血样以测定血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）和碱性磷酸酶（ALP）水平。提取肝脏进行组织学检查、生化测定和实时 PCR 研究。评估肝组织中的丙二醛（MDA）、谷胱甘肽（GSH）、蛋白羰基（PC）、一氧化氮（NO）水平、过氧化氢酶（CAT）、超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GPx）和髓过氧化物酶（MPO）活性。此外，还使用实时 PCR 法测量肝组织中 SOD 和 PGx 的表达。结果表明，MTX 给药显著增加 AST、ALT 和 ALP 水平（均 p<0.001）。它还增加 MDA、PC、NO 水平和 MPO 活性（p<0.001、p<0.01、p<0.05 和 p<0.01 分别）。此外，MTX 降低肝 GSH 水平、SOD、GPx 和 CAT 活性（均 p<0.001）。10 天的 BBR 预处理可预防其中一些变化。血清 AST 和 ALT 水平降低（均 p<0.001）。肝 MDA 水平降低（p<0.001），GSH 水平以及 GPx 活性增加（p<0.05 和 p<0.01 分别）。我们的结果表明，BBR 可能通过改善生化和氧化应激指标对 MTX 诱导的肝毒性具有有益作用。
