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Citrinin, a fungal toxin, induces apoptosis via mitochondrial pathway

The Mycotoxin citrinin (CTN) is a secondary metabolite produced by several fungal species that belong mainly to the genus Penicillium and Monascus. It is widely considered as a hazard contaminant of foods// and feeds, including corn, wheat, rice, barley and nuts, and is known to be cytotoxic and genotoxic to various mammalian cells. CTN has been suggested as a causative factor in renal disease among poultry, pigs, dogs and rats.

Many fungal toxins, including ochratoxin A, trichothecene, fumonisin B1, are known to trigger cellular apoptosis, which is a highly regulated cellular process, essential for normal development and the maintenance of homeostasis. The cytotoxic effects of these mycotoxins on animal tissues and cultured cells are thought to correlate with their apoptosis-inducing ability.

A recent paper, to be published in Toxicology Letters (available online 23 September 2005), reports that CTN induces apoptosis through the mitochondria-dependent pathway in human promyelocytic leukemia cells (HL-60) and the process is not directly correlated with cellular oxidative stress.

For the study, human promyelocytic leukemia (HL-60) cells were chosen to identify the apoptotic process induced by CTN. Morphological evidence of apoptosis, including nuclei fragmentation and DNA laddering formation, was clearly observed 24 h after exposure to CTN.

The apoptosis triggered by CTN in HL-60 was accompanied by the cytochrome c release from mitochondria to cytoplasm. The presence of antioxidants in cultures did not effectively suppress CTN-induced cytotoxicity and caspase-3 activity.

These findings suggest that CTN induces apoptosis in HL-60 cells by stimulating cytochrome c release followed by activation of multiple caspases, but oxidative stress may not play a role in the apoptotic process.

Researchers from the Chung Shan Medical University, Department of Life Sciences, Taiwan have combined morphological and biochemical techniques to demonstrate that CTN, a frequently found mycotoxin in food and feed, induced apoptosis in HL-60 cells through the intrinsic pathway, and oxidative stress was not directly involved in the apoptotic process.

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