Dose-dependent reduction of 3,2′-dimethyl-4-aminobiphenyl-derived DNA adducts in colon and liver of rats administered celecoxib

Abstract

Colon cancer is second leading cause of cancer-related deaths in Western countries. Diet and smoking, which contain aromatic and heterocyclic amines, are major risk factors for colon cancer. Colorectal cancers have a natural history of long latency and therefore provide ample opportunities for effective chemoprevention. 3,2'-Dimethyl-4-aminobiphenyl (DMABP) is an experimental aromatic amine that causes cancer in rat colon and serves as an experimental model for arylamine and heterocyclic amine mutagens derived from diet and smoking. In this study, we investigated the effects of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor on DMABP-induced DNA adduct formation in rat liver and colon. Male F-344 rats (5-weeks old) were provided free access to modified AIN-76A rat chow containing 0 (control), 500, 1000, or 1500 ppm celecoxib. Two weeks later, the rats received a subcutaneous injection of 100 mg/kg DMABP in peanut oil. Two days after DMABP treatment, the rats were killed and DMABP-derived adducts were analyzed in colon and liver DNA by butanol extraction-mediated 32 P-postlabeling. Two major DNA adducts, identified as dG-C8-DMABP and dG-N 2 -DMABP, were detected in liver and colon of rats treated with DMABP. These DNA adducts were diminished approximately 35-40% with 500 ppm and 65-70% with 1,000 ppm celecoxib. In the colon, no further decline in DNA adducts was observed at 1500 ppm. The same DMABP-DNA adducts also were detected in the liver and were also diminished by celecoxib treatment. The reduction in DMABP-DNA adduct levels in celecoxib-treated animals provides further support for celecoxib as a chemopreventive agent for colorectal cancer.

Meat Consumption, Nonsteroidal Anti-Inflammatory Drug Use, and Mortality among Colorectal Cancer Patients in the California Teachers Study

“…In a case-control study, heterocyclic amines were associated with risk of colorectal adenomas (48). Interestingly, the COX-2 selective NSAID celecoxib has been shown to decrease heterocyclic amine-induced colonic mutagenicity in experimental rats (49). Late effects on CRC progression or survival attributed to these carcinogenic agents are unknown.…”

Chemoprevention of Arylamine-Induced Colorectal Aberrant Crypts

“…Docosahexanenoic acid treatment reduced formation and growth of 2-amino-1-methyl-6phenylimidazo(4,5-b) pyridine-induced ACF in rat colon (32). Recently, celecoxib was shown to reduce DNA adduct levels in colon of rats treated with DMABP (33). Thus, we hypothesized that sulindac and celecoxib as inhibitors of COX-1 and/or COX-2 would reduce colon AC/ACF resulting from exposure to DMABP.…”

Experimental Murine Models for Colorectal Cancer Research

“…This study found that diets containing wheat bran and citrus fiber reduce the risk for DMAB-induced intestinal cancer and that the protection against CRC depends on the type of fiber. DMAB reacts with DNA through the formation of DNA adducts via N-hydroxylation, O-acetylation, and hydrolysis by cytochrome P450 [59].…”