Drug-Induced Protoporphyria in Beagle Dogs

Abstract

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.

Pathology in Practice

“…7 In mammals, synthesis of heme occurs in erythropoietic cells and in the hepatocytes of the liver. 9 The congenital form of the disease is caused by an inherited defect of uroporphyrinogen III cosynthase. 6 Congenital and acquired forms of porphyria in cattle, [10][11][12] swine, 13,14 sheep, 15 dogs, 5,9 cats, 4,6,16-18 fox squirrels, 19 and mice 20 have been described.…”

“…9 The congenital form of the disease is caused by an inherited defect of uroporphyrinogen III cosynthase. 6 Congenital and acquired forms of porphyria in cattle, [10][11][12] swine, 13,14 sheep, 15 dogs, 5,9 cats, 4,6,16-18 fox squirrels, 19 and mice 20 have been described. Although most forms of porphyria are inherited, acquired forms (ie, experimentally induced with drugs or chemicals) of porphyria have been established in dogs, 9 calves, 21 Figure 2-Photographs of a femur from a healthy 2-month-old kitten that died following blunt force trauma (control specimen; A) and a femur from the kitten in Figure 1 (B and C).…”

“…2,25 Uroporphyrin and coproporphyrin are water soluble and excreted via bile and feces as well as urine. 9 It was initially believed that porphyria was inherited as an autosomal dominant trait, 4,26 but porphyria has since been shown to be inherited as an autosomal recessive trait. 6 Clinically, porphyria in cats correlates most closely with congenital erythropoietic porphyria in humans, with the exception of photosensitivity, which has not been reported for cats.…”