Effect of Environmental Toxicants on NO Formation

Because of the redox nature of the NOS multienzyme complex, studies have been extended to heavy and transition metals. In one of our recent studies, we investigated the effects of heavy and transition metals on cNOS activity (Mittal et al., 1995). When brain cytosolic preparations were prein- 

TABLE III Inhibition Constants of Brain Nitric Oxide Synthase (NOS) with Various Cations  

Heavy metal cations (e.g., Pb, Cd, and Hg ), on the other hand, could directly bind either to the enzyme protein, inducing an unfavorable conformation change, or to calmodulin, effecting calcium-calmodulin interaction. 

One recent study with endothelial cell cultures demonstrated that increasing concentrations of extracellular calcium ion abolished Pb -mediated inhibition of NO production (Blazka et al., 1994). While these studies were in progress, another laboratory reported the inhibitory influence of several heavy metals in an in vitro study of cNOS (Joshi and Desaiah, 1994). The data described in our studies corroborate the results and conclusions of the published reports and provide new information on additional cations with possible toxicological implications. 

It is apparent from the foregoing discussion that the NO-NOS system represents a complex bioregulatory entity involved in many organ systems. It triggers constitutive as well as adaptive physiological responses. While the ultimate effect of NO may be determined by its interaction with different target systems, the synthesis of NO itself appears to be a crucial step in this pathway. We conclude from our studies and those of others that NO radical is probably one of the normal by-products of the oxygen metabolism. This is based on the facts that (1) the synthesis of NO is oxidative in nature, 

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