Submitted to: Meeting Abstract
Publication Type: Abstract only
Publication Acceptance Date: 3/20/2008
Publication Date: 3/20/2008
Citation: Haschek, W.M., Hsiao, S., Wicklow, D.T. 2008. The Fungal Metabolite, Pyrrocidine A, induces Apoptosis in HEPG2 Hepatocytes and PK15 Renal Cells [abstract]. Toxicological Sciences 86 (S-1): Abs. 2227. Interpretive Summary:
Technical Abstract: Pyrrocidines are polyketide-amino acid-derived antibiotics produced by Acremonium zeae, a prevalent seed-borne endophyte of corn. Pyrrocidines exhibit potent activity against Gram-positive bacteria, including drug resistant strains, and display significant activity against Candida albicans, as well as fumonisin and alfatoxin producing fungi. We have shown that pyrrocidines A and B are cytotoxic in two mammalian cell lines, HepG2 cells and PK15 cells, with pyrrocidine A more potent than pyrrocidine B. Morphologic changes were consistent with apoptosis. In this study, we examined the caspase-8 (an initiator in the extrinsic/receptor-mediated apoptotic pathway), caspase-9 (an initiator in the intrinsic apoptotic pathway), and caspase-3/7 activity (effectors of apoptosis), as well as the amount of released lactate dehydrogenase (LDH; compromised cell membrane integrity) and MTT formazan formed in the mitochondria (viability) at 1, 4, and 24 hours after addition of 25 ug pyrrocidine A/mL to cultured HepG2 and PK15 cells. Pyrrocidine A treatment caused an early decrease in mitochondria activity and activation of caspase-8/9 followed by activation of caspase 3/7 and LDH release in both cell types. These findings indicate that pyrrocidine A induced cytotoxicity is the result of apoptosis initiated through both the intrinsic and the receptor mediated apoptotic pathways. Given the toxicity of pyrrocidines in mammalian systems, in vivo studies are essential for risk assessment.