Acute, subchronic and chronic safety studies with genistein in rats
Acute, subchronic and chronic safety studies with genistein in rats
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DOI：
10.1016/j.fct.2005.05.021
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发表时间：
2006-01-01
影响因子：
4.3
通讯作者：
Bausch, J
中科院分区：
文献类型：
--
作者：
McClain, RM;Wolz, E;Bausch, J
染料木黄酮是一种植物雌激素，天然存在于饮食中，特别是在大豆食品中。基于流行病学证据，植物雌激素作为多种疾病和癌症的化学预防剂受到广泛关注。虽然大豆，其成分，如染料木素，已被消耗在高水平的几个亚洲人口没有明显的不良影响，已提出了关于潜在的不良影响，由于雌激素和其他activity.Safety研究染料木素进行了Wistar大鼠，包括两个急性研究，两个亚慢性（4周和13周）和慢性52周的饮食混合研究。在急性研究中，染料木黄酮的毒性较低。在剂量高达500 mg/kg/天的三项重复给药安全性研究中，染料木黄酮耐受性良好。在所有研究中，在500 mg/kg/天剂量下均观察到摄食量和体重增量减少。主要血液学结果为500 mg/ kg/天剂量组红细胞参数降低，伴网织红细胞代偿性增加。对于临床化学，除高剂量组雄性和雌性大鼠的γ谷氨酰转移酶轻微增加外，还有许多其他认为不具有毒理学意义的微小变化。尸检时，肉眼可见变化相对较少;在52周研究中，观察到高剂量组子宫扩张伴液体，给药组动物出现卵巢囊肿。500 mg/ kg/天高剂量组雄性大鼠的器官重量变化包括肾脏、脾脏、肾上腺和睾丸重量增加，雌性大鼠的器官重量变化包括肝脏、肾脏、脾脏、卵巢和子宫重量增加。在用染料木黄酮治疗4周和13周后，没有治疗相关的组织病理学发现。给药26周和52周后，在雌性生殖器官（卵巢和子宫）和雄性（附睾和前列腺）以及两种性别的骨骼、肾脏、心脏、肝脏和脾脏中观察到组织学变化。雄性动物给药52周后，500 mg/kg/天剂量组附睾上皮空泡化和50和500 mg/kg/天剂量组前列腺炎症的发生率较高。在雌性动物中，在50和500 mg/kg/天剂量组观察到子宫细胞学变化、鳞状上皮化生以及500 mg/kg/天剂量组观察到增生。此外，在500 mg/kg/天剂量下观察到子宫积水和阴道异常，包括无腹或间情期阴道粘膜伴阴道粘液化、上皮增生和多灶性囊性变性。50和500 mg/kg/天剂量组动物的卵巢萎缩严重程度增加。在50和500 mg/kg/天沿着剂量组雄性和雌性大鼠中观察到骨硬化症（骨质增生），同时脾脏髓外造血代偿性增加;雌性受影响程度大于雄性。在500 mg/kg/day.It的动物中，肝细胞肥大和最小胆管增生的发生率较高，可以得出结论，在这些研究中，几乎所有的治疗相关的发现都与染料木黄酮作为植物雌激素的雌激素特性有关，并且预计会发生与雌激素活性的化合物。认为与肾脏相关的变化本质上是功能性的，因此不是不良反应。这些研究中的大多数结果仅限于500 mg/kg/天的高剂量，并且是可逆的。在50 mg/kg/天剂量下观察到的少数结果相对较小，鉴于作用的功能（经尿道介导）性质，认为不是不良反应。极轻微胆管增生的发生率增加和γ谷氨酰转移酶轻微升高表明500 mg/kg/天高剂量下存在轻度肝脏效应。基于在500 mg/kg/天的高剂量下存在轻度肝脏效应，认为染料木黄酮的无明显不良作用水平（NOAEL）为50 mg/kg/天。基于较高剂量下经尿道诱导的功能变化，认为无明显作用水平（诺埃尔）为5 mg/kg/天。(c)2005爱思唯尔有限公司保留所有权利。
Genistein is a phytoestrogen that occurs naturally in the diet, especially in soy based foods. There is wide spread interest in phytoestrogens as chemopreventive agents for a variety of diseases and cancers based on epidentiologic evidence. Although soy, and its constituents such as genistein, have been consumed at high levels in several Asian populations without apparent adverse effects, concern has been raised about potential adverse effects due to the estrogenic and other activities.Safety studies with genistein were conducted in the Wistar rat including two acute studies, two subchronic (4 weeks and 13 weeks) and a chronic 52-week dietary admix study. In the acute studies, genistein had a low order of toxicity. In the three repeated dose safety studies at doses up to 500 mg/kg/day, genistein was well tolerated. In all of the studies, decreased food consumption and body weight gain were observed at 500 mg/kg/day. The main hematological findings were decreased red blood cell parameters at 500 mg/ kg/day with a compensatory increase in reticulocytes. For clinical chemistry, with the exception of a slight increase in gamma glutamyl transferase in male and female rats at the high dose, there were a number of other minor changes considered not toxicologically significant. At necropsy, there were relatively few macroscopic changes; in the 52-week study, dilation of the uterus with fluid at the high dose and cysts of the ovaries in treated animals were observed. Organ weight changes in male rats at the high dose of 500 mg/ kg/day included increased kidney, spleen, adrenal and testes weights and for females included, increased liver, kidney, spleen, ovary and uterus weights. After 4 and 13 weeks of treatment with genistein, there were no treatment related histopathologic findings. After 26 and 52 weeks of treatment, histological changes were seen in the female reproductive organs (ovaries and uterus), and in males (epididymides and prostate), and bone, kidneys, heart, liver and spleen in both sexes. After 52 weeks of treatment of males, vacuolation of the epididymal epithelium at 500 mg/kg/day and inflammation of the prostate were recorded at a higher incidence at 50 and 500 mg/kg/day. In females, cytological changes in the uterus, squamous metaplasia at 50 and 500 mg/kg/day and hyperplasia at 500 mg/kg/day were observed. Furthermore, hydrometra of the uterus and findings in the vagina consisting of anestric or diestrus vaginal mucosa with vaginal mucification, hyperplastic epithelium and multifocal cystic degeneration were noted at 500 mg/kg/day. Atrophy of the ovaries increased in severity in animals at 50 and 500 mg/kg/day. Osteopetrosis (hyperostosis) was observed in male and female rats at 50 and 500 mg/kg/day along with a compensatory increase in extramedullary hemopoiesis in the spleen; females were more affected than males. Hepatocellular hypertrophy and minimal bile duct proliferation were recorded at a higher incidence in animals at 500 mg/kg/day.It is concluded that almost all of the treatment related findings in these studies are related to the estrogenic properties of genistein as a phytoestrogen and would be expected to occur with a compound with estrogenic activity. The hormonally related changes were considered to be functional in nature and thus not adverse effects. Most of the findings in these studies were limited to the high dose of 500 mg/kg/day and were reversible. The few findings observed at 50 mg/kg/day were relatively minor and in view of the functional (hormonally mediated) nature of the effects, were considered not adverse effects. The increased incidence of minimal bile duct proliferation and slightly increased gamma glutamyl transferase are indicative of a mild hepatic effect at the high dose of 500 mg/kg/day. The no observed adverse effect level (NOAEL) of genistein is considered to be 50 mg/kg/day based on the presence of mild hepatic effects at the high dose of 500 mg/kg/day. The no observed effect level (NOEL) is considered to be 5 mg/kg/day based on the hormonally induced functional changes at higher doses. (c) 2005 Elsevier Ltd. All rights reserved.