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.
Zenk
P
P
Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence.
Brinkman
R
R
Gammal
L
L
Penka
V
V
Bresnahan
J
J
Wiley
R
R
Traiger
G
G
D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D001806:Blood Urea Nitrogen; D004347:Drug Interactions; D005663:Furans / Q000493:pharmacokinetics / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010424:Pentobarbital / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000378:metabolism; D010130:p-Aminohippuric Acid / Q000493:pharmacokinetics
D005663:Furans; D010424:Pentobarbital; D013936:Thymidine; D010130:p-Aminohippuric Acid