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Published on: January 19, 2010
Drug enterocyte adducts: possible causal factor for diclofenac enteropathy in rats
C R Atchison1, A B West, A Balakumaran
1Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Reactive metabolites of diclofenac form adducts in enterocytes, causing dose-dependent small intestine ulcers. This molecular change precedes and correlates with ulceration, suggesting a causal role in diclofenac enteropathy.
Area of Science:
- Gastroenterology
- Toxicology
- Molecular Biology
Background:
- Enteropathy is a common complication of nonsteroidal anti-inflammatory drugs (NSAIDs) like diclofenac.
- The precise mechanism underlying NSAID-induced enteropathy remains largely unknown.
- Reactive metabolites forming adducts with cellular macromolecules are a potential mechanism, observed previously in the liver.
Purpose of the Study:
- To investigate the potential role of diclofenac-induced adduct formation in enterocytes.
- To determine if these adducts precede and correlate with the development of enteropathy.
- To elucidate the mechanism of diclofenac enteropathy using immunohistochemistry.
Main Methods:
- Rats were administered varying doses of diclofenac (10-100 mg/kg) orally.
- Gastrointestinal tracts were examined for ulcer number and area at 1-24 hours post-treatment.
- Immunohistochemistry was employed to detect and assess the distribution and intensity of diclofenac adducts in intestinal tissues.
Main Results:
- Diclofenac treatment caused dose-dependent formation of both adducts and ulcers exclusively in the small intestine.
- Adduct formation within enterocytes occurred within 1 hour, translocated to the brush border, and preceded ulceration and vascular leakage.
- Adducts and ulcers showed a parallel distribution, with higher intensity in the 3rd and 5th intestinal quintiles.
Conclusions:
- Diclofenac treatment leads to the formation of drug adducts within enterocytes.
- The temporal and spatial correlation between adduct formation and ulceration suggests a causal link.
- Drug adduct formation is implicated as a key mechanism in the pathogenesis of diclofenac enteropathy.
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