|[Frontiers in Bioscience 2, d189-196, May 1, 1997]|
INTERACTIONS BETWEEN SUPEROXIDE AND NITRIC OXIDE: IMPLICATIONS IN DNA DAMAGE AND MUTAGENESIS|
David Jourd'heuil, David Kang and Matthew B. Grisham
Department of Molecular and Cellular Physiology, Louisiana State University Medical Center, Shreveport, LA 71130, USA
Received 4/3/97; Accepted 4/7/97; On-line 5/1/97
Active episodes of ulcerative colitis are characterized by infiltration of large numbers of phagocytic leukocytes into the mucosal interstitium. This enhanced inflammatory infiltrate is accompanied by extensive injury to the mucosa. A growing body of clinical and experimental data suggests that severelong-standing inflammation of the colon is associated with an increase risk of colorectal cancer (1-3). In addition, investigators have shown that inflammation enhances the formation of colonic tumors in experimental animals given known carcinogens (4,5). Despite these studies, the mechanisms by which inflammation promotes tumor formation remain poorly understood. It has been suggested that certain leukocyte-derived products may act as endogenous carcinogens or tumor promotors in vivo (1). Recent studies have shown that neutrophils and macrophages are capable of generating the free radical nitric oxide (NO) via an L-arginine-dependent pathway (6-9). Nitric oxide is unstable in the presence of molecular oxygen and will rapidly and spontaneously decompose to yield a variety of nitrogen oxides that are known to be potent nitrosating agents that will N-nitrosate primary and secondary amines to yield carcinogenic nitrosamines (10). Secondary nitrosamines require metabolic activation to yield alkylating agents that have been shown to activate certain oncogenes via the covalent modification of certain DNA bases (11). Nitrosative deamination of primary aromatic amines has been another suggested pathway by which NO-derived N-nitrosating agents produce transition and transversion mutations (12). The objective of this review is to discuss the chemical interactions between superoxide (O2-) and NO and to exmamine how these interactions may be involved in inflammation-induced DNA damage and mutagenesis.