Targeted Deletion of Kynurenine 3-Monooxygenase in Mice.

Kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the kynurenine pathway (KP) of tryptophan degradation, has been suggested to play a major role in physiological and pathological events involving bioactive KP metabolites. To explore this role in greater detail, we generated mice with a targeted genetic disruption of Kmo and present here the first biochemical and neurochemical characterization of these mutant animals. Kmo-/- mice lacked KMO activity but showed no obvious abnormalities in the activity of four additional KP enzymes/tested. As expected, Kmo-/- mice showed substantial reductions in the levels of its enzymatic product, 3-hydroxykynurenine, in liver, brain, and plasma. Compared with wild-type animals, the levels of the downstream metabolite quinolinic acid were also greatly decreased in liver and plasma of the mutant mice but surprisingly were only slightly reduced (by 20%) in the brain. The levels of three other KP metabolites: kynurenine, kynurenic acid, and anthranilic acid, were substantially, but differentially, elevated in the liver, brain, and plasma of Kmo-/- mice, whereas the liver and brain content of the major end product of the enzymatic cascade, NAD+, did not differ between Kmo and wild-type animals. When assessed by in vivo microdialysis, extracellular kynurenic acid levels were found to be significantly elevated in the brains of Kmo-/- mice. Taken together, these results provide further evidence that KMO plays a key regulatory role in the KP and indicate that Kmo-/- mice will be useful for studying tissue-specific functions of individual KP metabolites in health and disease. [ABSTRACT FROM AUTHOR]