Persistence and Reversibility of the Elevation in Free Sphingoid Bases Induced by Fumonisin Inhibition of Ceramide Synthase

Abstract

These studies determined (1) the time course for sphingoid base elevation in the small intestines, liver, and kidney of mice following a single 25 mg/kg body weight (bw) oral dose (high dose) of fumonisin B(1) (FB(1)), (2) the minimum threshold dose of FB(1) that would prolong the elevated sphingoid base concentration in kidney following the single high dose, and (3) the importance of the balance between the rate of sphingoid base biosynthesis and degradation in the persistence of sphingoid base accumulation. Following the high dose of FB(1), there was an increase in sphinganine in intestinal cells and liver that peaked at 4 to 12 h and declined to near the control level by 48 h. In kidney, sphinganine peaked at 6-12 h but remained elevated until 72 h, approaching control levels at 96-120 h. Oral administration of 0.03 mg FB(1)/kg bw (low dose) for 5 days had no effect on the sphingoid bases in kidney. However, following an initial high dose, daily administration of the low dose prolonged the elevation in kidney sphinganine compared to mice receiving a single high dose. Thus, a single exposure to a high dose of FB(1) followed by daily exposure at low levels will prolong the elevation of sphinganine in kidney. In cultured renal cells FB(1) was rapidly eliminated, but elevated sphinganine was persistent. This persistence in renal cells was rapidly reversed in the presence of the serine palmitoyltransferase inhibitor (ISP-1), indicating that the persistence was due to differences in the rates of sphinganine biosynthesis and degradation. The in vivo persistence in kidney may be due to similar differences.

Fumonisinas: efeitos toxicológicos, mecanismo de ação e biomarcadores para avaliação da exposição

“…No entanto, a administração diária de baixas doses após uma única dose alta prolongou a elevação nos níveis de esfinganina renal em comparação aos camundongos que receberam uma única dose alta (ENONGENE et al, 2002).…”

“…O aumento prolongado de bases esfingóides livres em alguns tipos celulares pode ser devido a uma combinação da persistência da inibição da ceramida sintase, diferenças na cinética de biossíntese da Sa (atividade da serina palmitoiltransferase) e degradação (via esfinganina quinase) (ENONGENE et al, 2002).…”

“…Dentre estes eventos está a ativação de esfingomielinases, mediando a produção de ceramida, ativação da caspase, expressão de proteínas inibidoras da apoptose e ativação do fator nuclear κB (NFκΒ). É possível deste modo que as vias dependentes dos esfingolipídeos e TNF-α interajam para influenciar a toxicidade da FB 1 (VOSS et al, 2002).…”

Inducible nitric oxide has protective effect on fumonisin B1 hepatotoxicity in mice via modulation of sphingosine kinase

“…Livers were removed, weighed, and aliquots were fixed immediately in neutral 10% formalin or quickly frozen in liquid nitrogen and stored at −85°C until analysis. The time of sampling was based on our observations that effects of fumonisin B 1 decline rapidly after cessation of treatment (Enongene et al, 2002). Activities of plasma ALT and AST were determined using a Hitachi 912 Automatic Analyzer (Roche Diagnostics, Indianapolis, IN).…”

Micotoxinas en la Salud Pública

“…El mecanismo de acción tóxica de las fumonisinas involucra la inhibición de la enzima ceramida sintetasa (30), generando un acúmulo de las bases esfingiodes y una disminución de los esfingolípidos complejos (31,32). Se encuentra clasificada según la IARC dentro del grupo 2B (13,14).…”