Microsomal oxidative stress induced by NADPH is inhibited by nitrofurantoin redox biotranformation

Nitrofurantoin is used in the antibacterial therapy of the urinary tract. This therapy is associated with various adverse eff ects whose \nmechanisms remain unclear. Diverse studies show that the nitro reductive metabolism of nitrofurantoin leads to ROS generation. This \nreaction can be catalyzed by several reductases, including the cytochrome P450 (CYP450) reductase. Oxidative stress arising from this \nnitro reductive metabolism has been proposed as the mechanism underlying the adverse eff ects associated with nitrofurantoin. There is, \nhowever, an apparent paradox between these fi ndings and the ability of nitrofurantoin to inhibit lipid peroxidation provoked by NADPH \nin rat liver microsomes. This work was aimed to show the potential contribution of diff erent enzymatic systems to the metabolism of \nthis drug in rat liver microsomes. Our results show that microsomal lipid peroxidation promoted by NADPH is inhibited by nitrofurantoin in a concentration-dependent manner. This suggests that the consumption of NADPH in microsomes can be competitively promoted by lipid peroxidation and nitrofurantoin metabolism. The incubation of microsomes with NADPH and nitrofurantoin generated \n1-aminohidantoin. In addition, the biotransformation of a classical substrate of CYP450 oxidative system was competitively inhibited \nby nitrofurantoin. These results suggest that nitrofurantoin is metabolized through CYP450 system. Data are discussed in terms of the in \nvitro redox metabolism of nitrofurantoin.