Atchison C R, West A B, Balakumaran A, Hargus S J, Pohl L R, Daiker D H, Aronson J F, Hoffmann W E, Shipp B K, Treinen-Moslen M
Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Gastroenterology. 2000 Dec;119(6):1537-47. doi: 10.1053/gast.2000.20186.
BACKGROUND & AIMS: Enteropathy is a frequent complication of diclofenac and other nonsteroidal anti-inflammatory drugs, yet little is known about the underlying mechanism. One possibility is that reactive metabolites of diclofenac form adducts with enterocyte macromolecules, as previously shown for liver. We addressed this possibility by using immunohistochemistry to detect diclofenac adducts.
Rats were treated orally with diclofenac (10-100 mg/kg) and killed after 1-24 hours, and their gastrointestinal (GI) tracts were evaluated for ulcer number and area. Adduct distribution and intensity were assessed by immunohistochemistry by using a technique to simultaneously process and stain multiple intestinal rings.
Drug treatment led to dose-dependent formation of both adducts and ulcers only in small intestine and only in animals with intact enterohepatic circulation. Adducts formed within enterocytes by 1 hour, translocated to the brush border, preceded ulceration and vascular protein leakage, and were intense at sites of ulceration. Adducts and ulcers exhibited a parallel distribution within intestinal quintiles: 3rd > 5th >> 1st.
Diclofenac treatment resulted in the formation of drug adducts in enterocytes. Because this molecular change occurred before ulceration, was dose dependent, and exhibited concordant distribution with extent of ulceration, the results suggest a causal role for drug adduct formation in diclofenac enteropathy.
肠病是双氯芬酸及其他非甾体抗炎药常见的并发症，但其潜在机制尚不清楚。一种可能性是双氯芬酸的反应性代谢产物与肠上皮细胞大分子形成加合物，如先前在肝脏中所显示的那样。我们通过免疫组织化学检测双氯芬酸加合物来探讨这种可能性。
给大鼠口服双氯芬酸（10 - 100mg/kg），1 - 24小时后处死，评估其胃肠道的溃疡数量和面积。采用同时处理和染色多个肠环的技术，通过免疫组织化学评估加合物的分布和强度。
药物治疗仅在小肠且仅在肝肠循环完整的动物中导致加合物和溃疡的剂量依赖性形成。加合物在1小时内在肠上皮细胞内形成，转移至刷状缘，先于溃疡和血管蛋白渗漏出现，且在溃疡部位强烈。加合物和溃疡在肠段五分位数内呈现平行分布：第3段>第5段>>第1段。
双氯芬酸治疗导致肠上皮细胞中药物加合物的形成。由于这种分子变化在溃疡形成之前发生，具有剂量依赖性，且与溃疡程度呈现一致分布，结果表明药物加合物形成在双氯芬酸肠病中起因果作用。
