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Toxicologic Pathology
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Articles

Drug-Induced Protoporphyria in Beagle Dogs

Sylvia W. M Greijdanus-van der Putten, Eric van Esch, Jan Kamerman, Leo A. P. Ballering, Diels J. van den Dobbelsteen and Eveline P. C. T de Rijk

Organon, Department of Toxicology and Drug Disposition, Oss, The Netherlands

Correspondence: Address correspondence to: Sylvia W. M. Greijdanus-van der Putten, Organon, Department of Toxicology and Drug Disposition, P.O. Box 20, 5340 BH Oss, The Netherlands; e-mail:sylvia.greijdanus{at}organon.com

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.

Key Words: Dog • drug-induced • liver • pigment deposits • protoporphyria • porphyria

Toxicologic Pathology, Vol. 33, No. 6, 720-725 (2005)
DOI: 10.1080/01926230500351392
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