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Toxicologic Pathology
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Toxicologic Lesions Associated with Two Related Inhibitors of Oxidosqualene Cyclase in the Dog and Mouse

Ian T. Pyrah

Safety Assessment, Alderley, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom

Adam Kalinowski

Safety Assessment, Alderley, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom

David Jackson

Safety Assessment, Alderley, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom

Wendy Davies

Safety Assessment, Alderley, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom

Stewart Davis

Safety Assessment, Alderley, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom

Andrew Aldridge

Safety Assessment, Alderley, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom

Peter Greaves

Safety Assessment, Alderley, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom

Two novel hypolipidaemic agents, both members of the aminopyrimidine series, with a mode of action of inhibition of oxidosqualene cyclase (OSC), were administered orally to dogs and mice for 14 and 28 days. Both compounds produced a similar spectrum of pathologic changes. In dogs, the agents produced equatorial single cell necrosis and cataract in the lens (also observed clinically); atrophy, ulceration, and infl ammation of the cornea; hyperkeratosis, acanthosis, hair papillary atrophy, and infl ammation of the skin; and epithelial degeneration and sperm granuloma in the epididymides. One female dog showed signs of liver toxicity. In mice, severe cataract formation was seen with both compounds, and liver toxicity was produced by one of the compounds. The severity and speed of onset of the cataract formation were very marked. The changes seen were dissimilar to those reported with the most commonly used class of hypolipidaemic agents in the clinic, the hydroxymethy l glutaryl coenzyme A (HMGCoA) reductase inhibitors but were reminiscent of those reported for the hypolipidaemic agent Triparanol, which was predictive of toxicity seen in man.

Key Words: Cataract • hair loss • hypolipidaemic agent • keratitis • sperm granuloma • hyperkeratosis.

Toxicologic Pathology, Vol. 29, No. 2, 174-179 (2001)
DOI: 10.1080/019262301317052440
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