Toxicity of alkyldihydrofurans to metabolically active organs in the mouse

Alkylfurans inflict toxicity in several mammalian species to lung, liver and kidney. Organ specificity of the alkylfurans is a sensitive function of the nature of the alkyl group. To determine if this toxicity requires an aromatic ring in the compound, we synthesized 4-methyl-2,3-dihydrofuran, 4-ethyl-2,3-dihydrofuran and 4-pentyl-2,3-dihydrofuran and determined their toxicity to lung, liver and kidney in mice. Lung damage was evaluated by light microscopy and the incorporation of [14C]thymidine into lung DNA. The results indicated that 4-methyl-2,3-dihydrofuran and 4-ethyl-2,3-dihydrofuran were toxic to the lung whereas 4-pentyl-2,3-dihydrofuran did not produce lung toxicity. Histological examination of liver sections revealed that 4-ethyl-2,3-dihydrofuran induced vacuolar degeneration of hepatocytes. Kidney toxicity was evaluated by light microscopy and determining plasma urea levels. Both 4-ethyl-2,3-dihydrofuran and 4-pentyl-2,3-dihydrofuran exhibited kidney toxicity, while equimolar doses of 4-methyl-2,3-dihydrofuran did not damage the kidney. A quantitative comparison of the nephrotoxicity of 4-pentyl-2,3-dihydrofuran with the corresponding aromatic compound 3-pentylfuran was made. We also sought to determine if renal injury resulting from these 2 agents is related to their oxidative metabolism. Uptake of organic ions by kidney slices and plasma urea nitrogen levels were used to assess renal function. 3-Pentylfuran caused greater renal injury than an equimolar dose of 4-pentyl-2,3-dihydrofuran. Phenobarbital pretreatment protected mice against 3-pentylfuran-induced nephrotoxicity. Cotreatment with piperonyl butoxide did not affect renal injury resulting from 3-pentylfuran. N-octylimidazole significantly reduced 3-pentylfuran-induced nephrotoxicity as well as that caused by 4-pentyl-2,3-dihydrofuran. These results point to metabolic activation as a basis for the nephrotoxicity induced by both compounds.