Drug-Induced Protoporphyria in Beagle Dogs

• Published in: Toxicologic pathology 2005-10, Vol.33 (6), p.720-725
• Main Authors: Greijdanus-van der Putten, Sylvia W. M, van Esch, Eric, Kamerman, Jan, Ballering, Leo A. P., van den Dobbelsteen, Diels J., T de Rijk, Eveline P. C.
• Format: Article
• Language: English
• Subjects: Alanine Transaminase - blood; Alkaline Phosphatase - blood; Animals; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - toxicity; Bilirubin - blood; Biological and medical sciences; Blood Coagulation - drug effects; Dermatology; Dogs; Dose-Response Relationship, Drug; Feces - chemistry; Female; Hyperplasia; Liver - drug effects; Liver - enzymology; Liver - pathology; Male; Medical sciences; Metabolic diseases; Organ Size - drug effects; Other metabolic disorders; Partial Thromboplastin Time; Pigments (porphyrias, hyperbilirubinemias...); Porphyrias, Hepatic - chemically induced; Porphyrias, Hepatic - metabolism; Porphyrias, Hepatic - pathology; Protoporphyrins - analysis; Protoporphyrins - metabolism; Skin involvement in other diseases. Miscellaneous. General aspects; Thymus Gland - drug effects; Thymus Gland - pathology; Toxicity Tests; Toxicology
• ISSN: 0192-6233; 1533-1601
• DOI: 10.1080/01926230500351392

As part of regulatory safety testing program, a 13-week oral toxicity study with a new antipsychotic drug candidate was performed in beagle dogs. During this study, dark red/brown feces were recorded in treated dogs and increases in liver parameters (alanine aminotransferase, alkaline phosphatase, bilirubin) were measured biochemically. At the end of the study, livers of high-dose (50 mg/kg) animals were (mottled) dark brown, sometimes with pale foci. Histopathological examination of these livers showed dark globular pigment deposits in the hepatocellular cytoplasm and within the bile canaliculi. Varying numbers of inflammatory cell infiltrates were additionally present in association with the deposits. These pigment deposits showed birefringency with characteristic “Maltese Cross”-like structures under polarized light. Electronmicroscopy revealed the typical, so-called “sunburst” pattern with radiating double-lined crystalline structures. These morphologic characteristics strongly indicated at the presence of porphyrins, which was definitely confirmed biochemically. Published reports of drug-induced hepatic porphyria in dogs are rare. The possible underlying mechanism in the dog and man is discussed.