Peroxygenase Metabolism of N-Acetylbenzidine by Prostaglandin H Synthase

Zenser, Terry V.; Lakshmi, Vijaya M.; Hsu, Fong‐Fu; Davis, Bernard B.

doi:10.1074/jbc.274.21.14850

Cited by 15 publications

(10 citation statements)

References 47 publications

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“…Studies have shown that the metabolic activation of primary and tertiary aromatic amines by prostaglandin H synthase does not involve the N-hydroxy intermediate step [44]. Studies on aromatic amines such as Nacetylbenzidine (ABZ) have shown that they can be metabolized through alternate pathways by peroxygenase to produce DNA adducts [45]. Comparison of the derived adduct with synthetic standards by HPLC confirmed the formation of dGp-ABZ by this mechanism [46].…”

Section: Discussionmentioning

confidence: 85%

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

Ravoori

Feng

Neale

et al. 2008

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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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.

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Section: Discussionmentioning

confidence: 85%

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

Ravoori

Feng

Neale

et al. 2008

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…Peroxidative activation of carcinogenic aromatic amines via prostaglandin H synthase has been reported (27,28). Recombinant human COX-1 and COX-2 enzymes have been shown to activate aromatic and heterocyclic amine carcinogens to intracellular electrophiles that bind covalently to DNA (29).…”

Section: Discussionmentioning

confidence: 99%

Chemoprevention of Arylamine-Induced Colorectal Aberrant Crypts

Feng

Neale

Doll

et al. 2008

Exp Biol Med (Maywood)

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Since recombinant human cyclooxygenase (COX) enzymes have been shown to activate environmental and dietary carcinogens implicated in human colorectal cancer etiology, we hypothesized that COX-2 inhibitors reduce arylamine-induced aberrant crypts (AC) and foci (ACF), preneoplastic lesions of colorectal cancer. Male weanling F344 inbred rats were fed modified AIN-76A control diet or the same diets supplemented with 320 ppm sulindac or 500, 1000, or 1500 ppm celecoxib. At 7 weeks of age, rats received a subcutaneous injection of 3,2′-dimethyl-4-aminobiphenyl (DMABP), an arylamine colon carcinogen, once weekly for two weeks. Ten weeks after the initial DMABP or vehicle treatment (at 17 weeks of age), rats were euthanized with CO 2 and the entire colorectum was removed and scored for ACF and AC. ACF possessing one to five AC were identified in the colorectum of rats administered DMABP, whereas no AC/ACF were identified in vehicle-treated controls. Significant reductions (p<0.001) in ACF and AC frequencies were observed in DMABP-treated rats supplemented with sulindac or celecoxib. Celecoxib reduced AC and ACF more than sulindac, but this difference was not significant (p >0.05). Reductions in both AC and ACF were highest following treatment with 1000 ppm celecoxib. These results provide additional experimental support for the chemopreventive effects of COX inhibitors in arylamineinduced colorectal cancer.

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“…Recognition of Zenser's ability to detect N 0 -hydroxy-N-acetylbenzidine on incubation with N-acetylbenzidine and PHS is not convincing that it would actually influence DNA modification in the urothelium. 5 If this were to be the case, one could argue that activation by PHS would be important for simple aromatic monoamines such as 2-aminofluorene and 2-aminonaphthalene.…”

Section: Dear Sirmentioning

confidence: 99%

“…5 If this were to be the case, one could argue that activation by PHS would be important for simple aromatic monoamines such as 2-aminofluorene and 2-aminonaphthalene.…”

Section: Dear Sirmentioning

confidence: 99%

Metabolic activation of benzidine

Wang

King²

2007

Intl Journal of Cancer

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Dear Sir,In reviewing the response by Carreon et al., 1 the framework of our conclusions regarding studies concerning benzidine can be summarized as follows.The mechanisms by which benzidine causes urinary bladder cancer is of scientific interest and, more importantly, as a public health issue. As stated in our original communication, 2 we agree with Carreon et al. that rapid acetylators appear to be at greater risk. 3 Our primary concern with their original paper and their response is that they give unwarranted strength to the idea that prostanglandin H synthase (PHS) is involved in the activation of N-acetylbenzidine to N 0 -hydroxy-N-acetylbenzidine in the urothelium, a target of benzidine in humans.We agree with their newly submitted proposed metabolic scheme that PHS is unlikely to produce a reactive metabolite in the urothelium. This is consistent with previous studies comparing the activation of benzidine and N-acetylbenzidine by PHS. The experimental evidence provided in Table I is from Morton et al. 4 As can be seen, PHS activation of N-acetylbenzidine is less than 1% that of benzidine, about one half that of 2-aminofluorene or 2-aminonaphthalene and slightly greater than 4-aminobiphenyl.Recognition of Zenser's ability to detect N 0 -hydroxy-N-acetylbenzidine on incubation with N-acetylbenzidine and PHS is not convincing that it would actually influence DNA modification in the urothelium. 5 If this were to be the case, one could argue that activation by PHS would be important for simple aromatic monoamines such as 2-aminofluorene and 2-aminonaphthalene.It is likely that most investigators in this area would agree that the presentation of N-oxidized aromatic amines to the urothelium is probably a crucial requirement for a carcinogenic outcome. A final metabolic transformation, such as the production of a reactive species by O-acetylation, would provide for chemical modification of DNA within the urothelial cell.The oxidized derivatives are generally believed to be derived from the urine; urinary diversion in the dog abolished the bladder carcinogenicity of 2-aminonaphthalene. 6 Much attention has been given to the possibility that urinary pH is involved in the stabilization, or activation, of various N-oxidized metabolites. The idea that the lower pH of urine might stabilize some N-oxidized metabolites would seem to be more important than the enhancement of modification of DNA by these metabolites. This comes from recognition that decreases in tightly regulated intracellular pH would be expected to compromise cellular viability and not provide for survival of modified cells capable of the development of tumors. Previous studies that have isolated benzidine-DNA adducts from exfoliated cells in the urine cannot exclude the possibility that these adducts came from acid-catalyzed reactions of hydroxylamines with nonviable cells that no longer had intact external cellular membranes. 7 We agree that the question of the identification of metabolites that are unstable, as with many of the postulated benzidine de...

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Peroxygenase Metabolism of N-Acetylbenzidine by Prostaglandin H Synthase

Cited by 15 publications

References 47 publications

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

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

Chemoprevention of Arylamine-Induced Colorectal Aberrant Crypts

Metabolic activation of benzidine

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