We report here the unexpected finding that recombinant or hepatic microsomal NADPH-cytochrome P450 reductase catalyzes the oxidative deformylation of a model xenobiotic aldehyde, 2-phenylpropionaldehyde, to the n-1 alcohol, 1-phenylethailol, in the absence of cytocbrome P450. The flavoprotein and NADPH are absolute requirements, and the reaction displays a dependence on time and oil NADPH and reductase concentration. Not surprisingly, the hydrophobic tail of the flavoprotein is not required for catalytic competence. The reductase domain of neuronal nitric oxide synthase is about 30% more active than P450 reductase, and neither flavoprotein catalyzes conversion of the aldehyde to the carboxylic acid, by far the predominant metabolite with P450s in a reconstituted system. Reductase-catalyzed deformylation is unaffected by metal ion chelators and oxygen radical scavengers, but is strongly inhibited by catalase, and the catalase-mediated inhibition is prevented by azide. These results, together with observed parallel increases in 1-phenylethanol and H2O2 formation as a function of NADPH concentration, are evidence that free H2O2 is rate-limiting in aldehyde deformylation by the flavoprotein reductases. This contrasts sharply with. the P450-catalyzed reaction, which is brought about by iron-bound peroxide that is inaccessible to catalase. (c) 2005 Elsevier Inc. All rights reserved.