Porphyrin accumulation in the harderian glands of female Syrian hamster results in mitochondrial damage and cell death

Abstract

Background: The Harderian glands of female Syrian hamsters contain very high concentrations of protoporphyrin (in the range of μg per mg of tissue) which accumulate in the tubulo‐alveoli of the gland. We have studied the process of synthesis, accumulation, and secretion of this cyclic compound by the secretory cells of the hamster Harderian glands. Methods: The animals used were female Syrian hamster of 15, 35, 75, 180, and 360 days of age. Items first examined were (1) percentage of the “clear cells,” (2) area occupied by intraluminal porphyrins, and (3) histological characteristics of “clear cells” by light and transmission electron microscopy (TEM). In a second study the total content of porphyrins was determined. Finally, the levels of mRNA for the enzyme aminolevulinate synthase (ALV‐S) were measured. Results: In the glands of female hamsters, both the tissue concentration and the intraluminal area occupied by protoporphyrin correlate with the appearance of a special type of cell (clear cells) which show signs of cell degeneration. In addition, the expression of the gene for ALV‐S, which is the limiting enzyme in porphyrin production, also parallels the relative number of clear cells. Analyzed under TEM, these clear cells display dilated mitochondria and short and swollen endoplasmic reticulum cisternae. In a late phase of necrosis, the nuclear envelope appears disorganized with scarce chromatin. The mitochondria undergo complete destruction, resulting in electron‐dense bacillar formations which progressively coalesce in large and dense areas of protoporphyrin. The cell dies after this accumulation, being secreted by a “cytogen” mechanism. Conclusions: In view of our results, the Harderian gland of female Syrian hamster may provide a useful model for the study of the mechanism by which the anomalous accumulation of protoporphyrin induces cell damage in human protoporphyria.