PORPHYRIN ACCUMULATION IN THE HARDERIAN GLANDS OF FEMALE SYRIAN-HAMSTER RESULTS IN MITOCHONDRIAL DAMAGE AND CELL-DEATH

Background: The Harderian glands of female Syrian hamsters contain ver y high concentrations of protoporphyrin (in the range Of mu g per mg o f 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 gland s. 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, an d (3) histological characteristics of ''clear cells'' by light and tra nsmission electron microscopy (TEM). In a second study the total conte nt of porphyrins was determined; Finally, the levels of mRNA for the e nzyme aminolevulinate synthase (ALV-S) were measured. Results: In the glands of female hamsters, both the tissue concentration and the intra luminal area occupied by protoporphyrin correlate with the appearance of a special type of cell (cigar cells) which show signs of cell degen eration. In addition, the expression of the gene for ALV-S, which is t he limiting enzyme in porphyrin production, also parallels the relativ e number of clear cells. Analyzed under TEM, these clear cells display dilated mitochondria and short and swollen endoplasmic reticulum cist ernae. In a late phase of necrosis, the nuclear envelope appears disor ganized with scarce chromatin. The mitochondria undergo complete destr uction, resulting in electron-dense bacillar formations which progress ively coalesce in large and dense areas of protoporphyrin. The cell di es after this accumulation, being secreted by a ''cytogen'' mechanism. Conclusions: In view of our results, the Harderian gland of female Sy rian hamster may provide a useful model for the study of the mechanism by which the anomalous accumulation of protoporphyrin induces cell da mage in human protoporphyria. (C) 1994 Wiley-Liss, Inc.