Liu Jing, Gupta Ramesh C, Goad John T, Karanth Subramanya, Pope Carey
Department of Physiological Sciences, Center for Veterinary Health Sciences, 264 McElroy Hall, Oklahoma State University, Stillwater, OK 74078, USA.
Toxicol Appl Pharmacol. 2007 Mar;219(2-3):106-13. doi: 10.1016/j.taap.2006.11.005. Epub 2006 Nov 11.
Glucose feeding can markedly exacerbate the toxicity of the anticholinesterase insecticide, parathion. We determined the effects of parathion on brain nitric oxide and its possible role in potentiation of toxicity by glucose feeding. Adult rats were given water or 15% glucose in water for 3 days and challenged with vehicle or parathion (18 mg/kg, s.c.) on day 4. Functional signs, plasma glucose and brain cholinesterase, citrulline (an indicator of nitric oxide production) and high-energy phosphates (HEPs) were measured 1-3 days after parathion. Glucose feeding exacerbated cholinergic toxicity. Parathion increased plasma glucose (15-33%) and decreased cortical cholinesterase activity (81-90%), with no significant differences between water and glucose treatment groups. In contrast, parathion increased brain regional citrulline (40-47%) and decreased HEPs (18-40%) in rats drinking water, with significantly greater changes in glucose-fed rats (248-363% increase and 31-61% decrease, respectively). We then studied the effects of inhibiting neuronal nitric oxide synthase (nNOS) by 7-nitroindazole (7NI, 30 mg/kg, i.p. x4) on parathion toxicity and its modulation by glucose feeding. Co-exposure to parathion and 7NI led to a marked increase in cholinergic signs of toxicity and lethality, regardless of glucose intake. Thus, glucose feeding enhanced the accumulation of brain nitric oxide following parathion exposure, but inhibition of nitric oxide synthesis was ineffective at counteracting increased parathion toxicity associated with glucose feeding. Evidence is therefore presented to suggest that nitric oxide may play both toxic and protective roles in cholinergic toxicity, and its precise contribution to modulation by glucose feeding requires further investigation.
给予葡萄糖会显著加剧抗胆碱酯酶杀虫剂对硫磷的毒性。我们确定了对硫磷对脑一氧化氮的影响及其在葡萄糖加剧毒性过程中可能发挥的作用。成年大鼠饮用纯水或含15%葡萄糖的水，持续3天，并于第4天给予溶剂对照或对硫磷（18mg/kg，皮下注射）。在给予对硫磷后1 - 3天，测量功能体征、血浆葡萄糖、脑胆碱酯酶、瓜氨酸（一氧化氮生成的指标）和高能磷酸盐（HEPs）。给予葡萄糖加剧了胆碱能毒性。对硫磷使血浆葡萄糖升高（15 - 33%），并使皮质胆碱酯酶活性降低（81 - 90%），纯水和葡萄糖处理组之间无显著差异。相比之下，对硫磷使饮用纯水的大鼠脑区瓜氨酸增加（40 - 47%），高能磷酸盐降低（18 - 40%），而给予葡萄糖的大鼠变化更为显著（分别增加248 - 363%和降低31 - 61%）。然后我们研究了用7 - 硝基吲唑（7NI，30mg/kg，腹腔注射×4次）抑制神经元型一氧化氮合酶（nNOS）对对硫磷毒性的影响及其受葡萄糖给予的调节作用。无论葡萄糖摄入量如何，对硫磷与7NI共同暴露均导致毒性和致死性的胆碱能体征显著增加。因此，给予葡萄糖增强了对硫磷暴露后脑一氧化氮的蓄积，但抑制一氧化氮合成并不能有效抵消与给予葡萄糖相关的对硫磷毒性增加。因此，有证据表明一氧化氮在胆碱能毒性中可能既发挥毒性作用又发挥保护作用，其对葡萄糖给予调节的确切作用需要进一步研究。
