Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang, PR China.
Drug Chem Toxicol. 2021 Mar;44(2):130-139. doi: 10.1080/01480545.2019.1566354. Epub 2019 Jul 1.
Diabetes mellitus is a significant global public health issue. The diabetic state not only precipitates chronic disease but also has the potential to change the toxicity of drugs and chemicals. Acrylonitrile (AN) is a potent neurotoxin widely used in industrial products. This study used a streptozotocin (STZ)-induced diabetic rat model to examine the role of cytochrome P450 2E1 (CYP2E1) in acute AN toxicity. The protective effect of phenethyl isothiocyanate (PEITC), a phytochemical inhibitor of CYP2E1, was also investigated. A higher incidence of convulsions and loss of the righting reflex, and decreased rates of survival, as well as elevated CYP2E1 activity, were observed in diabetic rats treated with AN when compared to those in non-diabetic rats, suggesting that diabetes confers susceptibility to the acute toxicity of AN. Pretreatment with PEITC (20-80 mg/kg) followed by AN injection alleviated the acute toxicity of AN in diabetic rats as evidenced by the decreased incidence of convulsions and loss of righting reflex, and increased rates of survival. PEITC pretreatment at 40 and 80 mg/kg decreased hepatic CYP2E1 activity in AN-exposed diabetic rats. PEITC pretreatment (20 mg/kg) increased the glutathione (GSH) content and glutathione S-transferase (GST) activity and further decreased ROS levels in AN-exposed diabetic rats. Collectively, STZ-induced diabetic rats were more sensitive to AN-induced acute toxicity mainly due to CYP2E1 induction, and PEITC pretreatment significantly alleviated the acute toxicity of AN in STZ-induced diabetic rats. PEITC might be considered as a potential effective chemo-preventive agent against AN-induced acute toxicity in individuals with an underlying diabetic condition.
糖尿病是一个重大的全球公共卫生问题。糖尿病状态不仅会引发慢性疾病，还有可能改变药物和化学物质的毒性。丙烯腈（AN）是一种广泛用于工业产品的强效神经毒素。本研究使用链脲佐菌素（STZ）诱导的糖尿病大鼠模型，研究细胞色素 P450 2E1（CYP2E1）在丙烯腈急性毒性中的作用。还研究了 CYP2E1 抑制剂苯乙基异硫氰酸酯（PEITC）的保护作用。与非糖尿病大鼠相比，糖尿病大鼠用 AN 处理后，癫痫发作和翻正反射丧失的发生率更高，存活率降低，CYP2E1 活性升高，这表明糖尿病使大鼠对 AN 的急性毒性敏感。用 PEITC（20-80mg/kg）预处理后再注射 AN，可减轻糖尿病大鼠的 AN 急性毒性，表现为癫痫发作和翻正反射丧失的发生率降低，存活率提高。PEITC 在 40 和 80mg/kg 预处理剂量下降低了 AN 暴露的糖尿病大鼠肝 CYP2E1 活性。PEITC 预处理（20mg/kg）增加了 AN 暴露的糖尿病大鼠的谷胱甘肽（GSH）含量和谷胱甘肽 S-转移酶（GST）活性，并进一步降低了 ROS 水平。总之，STZ 诱导的糖尿病大鼠对 AN 诱导的急性毒性更为敏感，主要是由于 CYP2E1 的诱导，PEITC 预处理可显著减轻 STZ 诱导的糖尿病大鼠的 AN 急性毒性。PEITC 可能被认为是一种有潜在应用价值的化学预防剂，可用于治疗糖尿病患者的 AN 急性毒性。
