Differential sensitivity of rat kidney and liver to fumonisin toxicity: organ-specific differences in toxin accumulation and sphingoid base metabolism.
Fumonisins (FBs) are mycotoxins in maize and are inhibitors of ceramide synthase (CS), the most likely proximate cause of FB toxicity. In liver and kidney, the primary target organs in FB-fed rats, inhibition of CS results in a marked increase in the ceramide precursor sphinganine (Sa). This study was conducted to investigate the differential time- and dose-dependent changes in Sa, sphingosine (So), sphinganine 1-phosphate (Sa-1-P), and sphingosine 1-phosphate (So-1-P) in kidney, liver, serum, and heart of male Sprague-Dawley rats (3-4 weeks old) fed diets containing 1.1, 13.5, and 88.6 mug/g of total FB for 10 days. The tissues were microscopically examined for the presence and severity of lesions consistent with FB exposure. There was a time- and dose-dependent increase in Sa in both liver and kidney, which was closely correlated with the tissue concentration of fumonisin B(1) (FB(1)) and histopathologic findings. However, the Sa alone greatly underestimated the degree of disruption of sphingolipid metabolism since accumulated Sa and So were quickly metabolized to Sa-1-P and So-1-P as evidenced by large increases in these metabolites in kidney but not in liver. The concentration of FB(1) in liver and kidney that first elicited an increase in Sa was similar in both tissues, however, over time, the kidney accumulated significantly more FB(1) (10x) and total Sa (Sa plus Sa-1-P) compared to liver. Thus, the relative sensitivity of male Sprague-Dawley rat kidney and liver is most likely a consequence of differences in the mechanisms responsible for both FB(1) uptake/clearance and Sa metabolism.
Riley
Ronald T
RT
Toxicology and Mycotoxin Research Unit, US Department of Agriculture/ARS, Athens, GA 30604-5677, USA. rriley@saa.ars.usda.gov
Voss
Kenneth A
KA
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D037341:Fumonisins / Q000493:pharmacokinetics / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013107:Sphingolipids / Q000378:metabolism*; D014018:Tissue Distribution
D037341:Fumonisins; D013107:Sphingolipids