title: Pharmacological antagonism of fumonisin B1 cytotoxicity in porcine renal epithelial cells (LLC-PK1): a model for reducing fumonisin-induced nephrotoxicity in vivo.
abstract: Fumonisin B1 is a mycotoxin commonly found on corn. It is hepatotoxic and nephrotoxic in domestic and experimental animals, and causes equine leukoencephalomalacia and porcine pulmonary oedema. It is a potent inhibitor of ceramide synthase. Inhibition leads to accumulation of free sphingoid bases in cells and tissues. In pig kidney epithelial cells (LLC-PK1), fumonisin B1 induces increased tumour necrosis factor alpha (TNFalpha) expression independent of the accumulation of sphingoid bases. The objective of this study was to investigate pharmacological approaches for intervening in fumonisin B1 toxicity using the LLC-PK1 cell model. The toxicity of fumonisin B1 was assayed using cell viability and lactate dehydrogenase (lactate dehydrogenase) release. Pretreatment of cells with myriocin, preventing sphinganine accumulates, prevented the fumonisin B1-induced decrease in cell viability and increased lactate dehydrogenase release. Modulation of adenosine receptor activity did not reduce the fumonisin B1 cytotoxicity. As with myriocin, silymarin pretreatment prevented the fumonisin B1-induced effects on cell viability and lactate dehydrogenase release. When added 6 or 24 hr after treatment of cells with fumonisin B1, both myriocin and silymarin reversed the decreased cell viability and suppressed the increased lactate dehydrogenase release. Myriocin, but not silymarin, blocked the accumulation of sphinganine in fumonisin B1-treated cells. Silymarin, unlike myriocin, induced expression of TNFalpha to an extent similar to fumonisin B1, but pretreatment with silymarin decreased the fumonisin B1-induced TNFalpha expression in LLC-PK1 cells. Results suggest that the mechanisms by which myriocin and silymarin protect renal cells are different, and silymarin potentially prevents fumonisin B1-induced toxicity by modulating TNFalpha expression or signals downstream of the inhibition of ceramide synthase.
authors.affiliation: Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens 30602-7389, USA.
authors.forename: Quanren
authors.initials: Q
authors.lastname: He
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Riley
authors.forename: Raghubir P
authors.initials: RP
authors.lastname: Sharma
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002274:Carcinogens, Environmental / Q000633:toxicity*; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005415:Flavins / Q000494:pharmacology; D037341:Fumonisins / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D018374:LLC-PK1 Cells; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051102:Serine C-Palmitoyltransferase; D012838:Silymarin / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D002274:Carcinogens, Environmental; D005229:Fatty Acids, Monounsaturated; D005415:Flavins; D037341:Fumonisins; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D012838:Silymarin; D014409:Tumor Necrosis Factor-alpha; C056426:CGS 24012; C056933:fumonisin B1; C008173:isoalloxazine; D007770:L-Lactate Dehydrogenase; D000217:Acyltransferases; D051102:Serine C-Palmitoyltransferase; D000241:Adenosine; D013110:Sphingosine; C005682:safingol; C001996:thermozymocidin