Fumonisin toxicity in a transgenic mouse model lacking the mdr 1a/1b P-glycoprotein genes

The toxicity of fumonisin B-1 (FB1) was investigated in male mdr1a/1b double knockout (MDRK) mice, lacking the drug-transporting P-glycoproteins. These transgenic animals are deficient in their blood:brain barrier and accumulate different drugs in brain and other tissues. The MDRK and their wild-type counterparts, FVB mice, were injected subcutaneously with 2.25 mg/kg per day of FB1 for 5 days and sampled one day after the last treatment in a protocol that has resulted in marked hepatic and renal damage in other strains. FB1 caused liver enlargement in both FVB and MDRK. Hematological parameters were not affected in either strain. Plasma levels of alanine aminotransferase and aspartate aminotransferase, measures of liver damage, were increased by FB1 in both FVB and MDRK mice. Histopathological evaluation of liver corroborated this finding. Kidney lesions were induced by FB1 in both types of mice. Concentrations of free sphingosine and sphinganine increased in liver and kidney of both strains after the FB1 treatment, although the increase in liver sphingoid bases was half as much in MDRK as compared to FVB. The levels of sphinganine-containing complex sphingolipids were increased in kidney. The levels of sphingosine-containing complex sphingolipids in kidney were unaffected by FB1 treatment but were significantly lower in control MDRK than in FVB mice. The levels of neurotransmitters and their metabolites were similarly affected in both strains by FB1, suggesting no influence of disrupted blood:brain barrier on FB1-induced neurotoxicity, In both strains, the liver mRNA for tumor necrosis factor alpha was increased: however, the increase was statistically significant only in FVB. It was apparent that mice deficient in P-glycoprotein do not exhibit greater sensitivity to FB1, the cellular or brain transport of FB1 appears to be independent of this multidrug transporting system. (C) 2000 Elsevier Science B,V. All rights reserved.