We have selected eight 5-nitrofurans for our studies. They range from the relatively nontoxic antibiotics, nitrofurantoin, nitrofurazone and furazolidone to several experimental mutanges/carcinogens. There is much circumstantial evidence that both the pharmacological and toxicological effects of these 5-nitrofurans are the consequence of the covalent binding of their activated reduced metabolites to DNA. Using the 14 C-5-nitrofurans we will study their metabolism and disposition in model systems using the isolated perfused rat liver and kidney. We will characterize the time course of the parent compound in the perfusate, bile and urine. We will also isolate, identify and delineate the time course of their metabolites in these biological fluids. Furthermore, we will quantitate the fraction bound to DNA and other nontarget biomacromolecules. We will isolate and identify the covalently bound DNA adducts and study the time course of binding to determine if the DNA is repaired. In addition, if necessary, we will use tissue slices, microsomal preparations and/or xanthine oxidase with and without added DNA to facilitate the collection of sufficient quantities of these metabolites and adducts for subsequent isolation and characterization. All perfusion studies will be carried out at concentrations where the kinetics are linear and also where kinetics are nonlinear (saturated). These studies will enable us to determine if the more toxic 5-nitrofurans form qualitatively/quantitatively different metabolites and adducts than the less toxic compounds. We will be able to determine both the tissue selectively and the biomacromolecular selectivity of these 5-nitrofurans. These studies to identify the metabolites, DNA adducts and tissue/biomacromolecular selectivity of the 5-nitrofurans will move us closer to our goal of providing direct evidence for the mechanism of both the similarities and the differences observed in the pharmacological and toxicological effects of these 5-nitrofurans.
| Hoener, B; Noach, A; Andrup, M et al. (1989) Nitrofurantoin produces oxidative stress and loss of glutathione and protein thiols in the isolated perfused rat liver. Pharmacology 38:363-73 |
| Streeter, A J; Hoener, B A (1988) Evidence for the involvement of a nitrenium ion in the covalent binding of nitrofurazone to DNA. Pharm Res 5:434-6 |
| Streeter, A J; Krueger, T R; Hoener, B A (1988) Oxidative metabolites of 5-nitrofurans. Pharmacology 36:283-8 |
| Sorrentino, D; Hoener, B A (1987) Hepatic disposition of clinically useful 5-nitrofurans. Biochem Pharmacol 36:2875-8 |
| Sorrentino, D; Bode, W; Hoener, B A (1987) Nitrofurazone disposition by perfused rat liver. Effect of dose size and glutathione depletion. Biochem Pharmacol 36:915-8 |
