Bromuconazole-induced hepatotoxicity is accompanied by upregulation of PXR/CYP3A1 and downregulation of CAR/CYP2B1 gene expression
Bromuconazole-induced hepatotoxicity is accompanied by upregulation of PXR/CYP3A1 and downregulation of CAR/CYP2B1 gene expression
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DOI：
10.1080/15376516.2017.1333555
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发表时间：
2017-01-01
影响因子：
3.2
通讯作者：
Saleh, Ayman A.
中科院分区：
文献类型：
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作者：
Abdelhadya, Doaa H.;Abu El-Magd, Mohammed;Saleh, Ayman A.
尽管溴菌唑被广泛用作粮食作物和水果的杀虫剂，但对其毒性影响的研究有限。在这里，我们评估了溴菌唑的肝毒性作用，采用经典的毒理学（生化分析和组织病理学检查）和基因为基础的分子方法。雄性大鼠经口或局部给予溴莫康唑，剂量相当于无明显不良反应水平（NOAEL）和1/10 LD_（50），连续90天。溴莫康唑增加肝酶（ALT、AST、ALP和ACP）活性和胆红素水平。它还诱导肝脏氧化应激，表现为肝脏超氧化物歧化酶（SOD）活性显著降低，丙二醛（MDA）水平显著升高。此外，溴莫康唑导致肝脏重量增加和坏死性变化（空泡化和肝细胞肥大）。它还强烈诱导PXR及其下游靶基因CYP 3A 1的表达以及CYP 3A 1的活性。然而，它抑制CAR及其下游靶标CYP 2B 1基因的表达，而不显著改变CYP 2B 1活性。总体而言，经口给药显示出比经皮给药更高的肝毒性作用和分子变化，所有变化均呈剂量依赖性。这是首次研究报告，溴莫康唑诱导的肝氧化损伤伴随着PXR/CYP 3A 1的上调和CAR/CYP 2B 1的下调。
Despite widespread use of bromuconazole as a pesticide for food crops and fruits, limited studies have been done to evaluate its toxic effects. Here, we evaluated the hepatotoxic effect of bromuconazole using classical toxicological (biochemical analysis and histopathological examination) and gene-based molecular methods. Male rats were treated either orally or topically with bromuconazole at doses equal to no observed adverse effect level (NOAEL) and 1/10 LD50 for 90d. Bromuconazole increased activities of liver enzymes (ALT, AST, ALP, and ACP), and levels of bilirubin. It also induced hepatic oxidative stress as evidenced by significant decrease in the activities of superoxide dismutase (SOD), and significant increase in levels of malondialdehyde (MDA) in liver. In addition, bromuconazole caused an increase in liver weights and necrobiotic changes (vacuolation and hepatocellular hypertrophy). It also strongly induced the expression of PXR and its downstream target CYP3A1 gene as well as the activity of CYP3A1. However, it inhibited the expression of CAR and its downstream target CYP2B1 gene without significant changing in CYP2B1 activity. Overall, the oral route showed higher hepatotoxic effect and molecular changes than the dermal route and all changes were dose dependent. This is the first investigation to report that bromuconazole-induced liver oxidative damage is accompanied by upregulation of PXR/CYP3A1 and downregulation of CAR/CYP2B1.