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Early Stellate Cell Activation and Veno-occlusive-disease (VOD)–like Hepatotoxicity in Dogs Treated with AR-H047108, an Imidazopyridine Proton Pump Inhibitor

¹ AstraZeneca R&D Södertälje, Södertälje, Sweden
² AstraZeneca R&D Mölndal, Mölndal, Sweden
³ AstraZeneca R&D Alderley Park, Macclesfield, United Kingdom
⁴ Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden

Correspondence: Anna-Lena Berg, Safety Assessment, Pathology, B681, AstraZeneca R&D Södertälje, S-151 85 Södertälje, Sweden; e-mail:anna-lena.berg{at}astrazeneca.com.

Dogs treated with AR-H047108, an imidazopyridine potassium competitive acid blocker (P-CAB), developed clinical signs of hepatic dysfunction as well as morphologically manifest hepatotoxicity in repeat-dose toxicity studies. An investigative one-month study was performed, with interim euthanasia after one and two weeks. A detailed histopathological and immunohistochemical characterization of the liver lesions was conducted, including markers for fibrosis, Kupffer cell activation, apoptosis, and endothelial injury. In addition, hepatic retinoid and procollagen 12 mRNA levels in livers of dogs treated with AR-H047108 were analyzed. The results showed an early inflammatory process in central veins and centrilobular areas, present after one week of treatment. This inflammatory reaction was paralleled by activation of stellate/Ito cells to myofibroblasts and was associated with sinusoidal and centrivenular fibrosis. The early activation of stellate cells coincided with a significant decrease in retinyl ester levels, and a significant increase in procollagen 12 mRNA levels, in the liver. At later time points (three and six months), there was marked sinusoidal fibrosis in centrilobular areas, as well as occlusion of central veins resulting from a combination of fibrosis and increased thickness of smooth muscle bundles in the vessel wall. The pattern of lesions suggests a veno-occlusive-disease (VOD)–like scenario, possibly linked to the imidazopyridine chemical structure of the compound facilitated by specific morphological features of the dog liver.

Key Words: veno-occlusive disease • VOD • hepatotoxicity • imidazopyridine • stellate cells • fibrosis

Abbreviations: ABC, avidin-biotin complex • ALP, alkaline phosphatase • ALT, alanine aminotransferase • AST, aspartate aminotransferase • APTT, activated partial thromboplastin time • AUC, area under the curve • DAB, diaminobenzidine • ET-1, endothelin-1 • H&E, hematoxylin and eosin • MT, Masson-Trichrome • PBR, peripheral benzodiazepine receptor • P-CABs, potassium competitive acid blockers • RNA, ribonucleic acid • SECs, sinusoidal endothelial cells • SMA, smooth muscle actin • TGFβ, transforming growth factor beta • TUNEL, TdT-mediated dUTP nick-end labeling • VOD, veno-occlusive disease

This version was published on July 1, 2008

Toxicologic Pathology, Vol. 36, No. 5, 727-737 (2008)
DOI: 10.1177/0192623308320802


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