Mutagenicity of Nitroaromatic Compounds

Nitrofurantoin is a commonly used urinary tract antibiotic prescribed to lactating woman. It is actively transported into human and rat milk by an unknown mechanism. Our group has demonstrated an important role of the breast cancer resistance protein (BCRP/ABCG2) in the secretion of xenotoxins into the milk. This ATP-binding cassette drug efflux transporter extrudes xenotoxins from cells in intestine, liver, mammary gland, and other organs, affecting the pharmacological and toxicological behavior of many compounds. We investigated whether Bcrp1 is involved in the pharmacokinetic profile of nitrofurantoin and its active secretion into the milk. Using polarized cell lines, we found that nitrofurantoin is efficiently transported by murine Bcrp1 and human BCRP. After oral administration of 10 mg/kg nitrofurantoin, the area under the plasma concentrationtime curve in Bcrp1 knockout mice was almost 4-fold higher than in wild-type mice (148.8 +/- 30.4 versus 37.5 +/- 6.8 min x microg/ml); and after i.v. administration (5 mg/kg), 2-fold higher (139.2 +/- 22.0 versus 73.9 +/- 9.0 min x microg/ml). Hepatobiliary excretion of nitrofurantoin was almost abolished in Bcrp1 knockout mice (9.6 +/- 3.2 versus 0.2 +/- 0.1% in wild-type and Bcrp1 knockout mice, respectively). The milk-to-plasma ratio of nitrofurantoin was almost 80 times higher in wild-type compared with Bcrp1 knockout lactating female mice (45.7 +/- 16.2 versus 0.6 +/- 0.1). Nitrofurantoin elimination via milk was quantitatively even higher than hepatobiliary elimination. We conclude that Bcrp1 is an important determinant for the bioavailability of nitrofurantoin and the main mechanism involved in its hepatobiliary excretion and secretion into the milk.

The breast cancer resistance protein (BCRP/ABCG2) affects pharmacokinetics, hepatobiliary excretion, and milk secretion of the antibiotic nitrofurantoin.

Summary 22 nitrofurans were tested for ability to induce revertants of E. coli WP2 and its uvrA - derivative from tryp - to tryp +. All proved to be mutagnic while two furan analogues (lacking the nitro- group) proved to be inactive. Test strains containing exrA - or recA - genes were not induced to mutate, suggesting that mutants arise in the other strains during repair of damage to DNA by the “error-prone” repair system. Two mutant strains isolated from WP 2 uvrA - on, the basis of resistance to nitrofurazone were not mutated by nitrofurazone or N -[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) indicating that the ultimate mutagens are likely to be a reduction product rather than the nitrofurans per se . Several of the nitrofurans cause induction of prophage leading to mass lysis in E. coli T44 (λ) a strain which is known to be very sensitive to heat and certain chemicals. Since two nitrofurans which have been reported to lack carcinogenic activity proved to be mutagnic, it is suggested that further assessment of the hazards that medical use of nitrofurans poses to humans should be further evaluated.

On the mutagenicity of nitrofurans

Nitroreduction of 5-nitrofuran derivatives by rat liver xanthine oxidase and reduced nicotinamide adenine dinucleotide phosphate-cytochrome c reductase.

R. C. Bender

Papers

Metabolic degradation of the nitrofurans.

Studies on the distribution and excretion of certain nitrofurans.