雷公藤甲素对大鼠肾上腺皮质毒性作用的时间节律性研究

Circadian rhythm investigation of the toxic effect of triptolide on adrenal cortex in rats

目的观察雷公藤甲素对大鼠肾上腺皮质的毒性作用并探讨其时间节律性,为临床合理用药、降低毒副反应提供实验依据。方法♂SD大鼠30只随机分为3组,包括空白对照组;雷公藤甲素早上用药组40μg.kg-1,qd,8am;雷公藤甲素晚上用药组40μg.kg-1,qd,8pm。连续灌胃7周后断头处死,测定大鼠血浆皮质醇含量,大鼠肾上腺HE染色和透射电镜观察,从功能和形态两方面探讨较长期和不同时辰服用雷公藤甲素对大鼠肾上腺皮质分泌功能的影响、中毒病理改变及其毒性机制。结果早上用药组大鼠血浆皮质醇含量明显低于空白对照组(P<0.05);晚上用药组大鼠血浆皮质醇含量与空白对照组比较无差异,与早上用药组比较差异有显著性(P<0.05)。HE染色观察:早上用药组肾上腺皮质较空白对照组变薄、结构不清、脂质空泡减少,晚上用药组肾上腺皮质较空白对照组略微增厚,束状带增宽,脂质空泡多。电镜观察:早上用药组皮质束状带细胞质中线粒体空泡变性,脂滴少,粗面内质网扩张,周边有核糖体;晚上用药组肾上腺皮质束状带细胞质中线粒体、脂滴、核糖体均较多。结论较长期服用雷公藤甲素对大鼠肾上腺皮质具有毒性作用,且其毒性作用具有时间节律性。

Aim To observe the toxic effects of triptolide（TP）on adrenal cortex of rats and its circadian rhythm for evidence of clinical medication reasonably and reduction of its toxic effects of this drug.Methods Thirty male Sprague-Dawley（SD）rats were randomized into groups of blank controls,morning medication of TP at dose of 40 μg·kg^-1.qd.or evening medication of TP at dose of 40 μg·kg^-1.qd.（n=10 for each）.After 7 successive intragastric administration of TP,the experimental animals were decapitated for detecting the level of plasma cortisol and observing the adrenal glands by HE staining and transmission electron microscope as well.Besides,the effects on the secretion function of adrenal cortex in rats,pathological change from toxicity and its mechanism were investigated concerning long-term effect and administration of TP at specific time by action and morphological difference.Results Lower serum level of cortisol was found in group of morning medication of TP as compared with the blank controls（P〈0.05）.The concentration remained no significant change with evening administration of TP,and yet,it was different from that of the morning medication（P〈0.05）.HE staining revealed that,in comparison with the controls,the adrenal cortex became atrophied,with dark structure and diminished lipid vacuoles in rats by morning medication,whereas it was found somewhat thickened,with widened zona fasciculata and more visible lipid vacuoles for the group of evening administration of TP.The electron microscope exposed degenerated vacuoles of intracytoplasmic mitochondria in the zona fasciculata of the adrenal gland,with fewer lipid droplets,dilated rough endoplasmic reticulum and ribosomes around for the morning medication group,and yet,the reverse condition was seen in the group undergone evening medication.Conclusion Comparatively chronic use of TP may impose toxicity on the adrenal cortex of rats and the toxic effect appears associated with temporal rhythm.