Comparative Tumorigenicity of the Environmental Pollutant 6-Nitrochrysene and Its Metabolites in the Rat Mammary Gland
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- 作者：Karam El-Bayoumy ; Dhimant Desai ; Telih Boyiri ; Jose Rosa ; Jacek Krzeminski ; Arun K. Sharma ; Brian Pittman ; and Shantu Amin
- 刊名：Chemical Research in Toxicology
- 出版年：2002
- 出版时间：July 2002
- 年：2002
- 卷：15
- 期：7
- 页码：972 - 978
- 全文大小：82K
- 年卷期：v.15,no.7(July 2002)
- ISSN：1520-5010
文摘
Human exposure to the class of nitropolynuclear aromatic hydrocarbons is via inhalationand/or ingestion. Therefore, one of the goals of this study was to determine the propensity ofthe environmental contaminant 6-nitrochrysene (6-NC) for inducing mammary cancer followingits oral administration to female CD rats. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine(PhIP), an established mammary carcinogen in the same animal model, was used as a positivecontrol and trioctanoin as a negative control. Thirty-day-old female CD rats were gavagedonce weekly for 8 weeks with 6-NC at 50, 25, or 12.5 
mol/rat or PhIP at 50 mol/rat in 500L of trioctanoin. Twenty-three weeks after the last carcinogen administration, rats weredecapitated, necropsied, and evaluated histologically. The most common mammary tumorswere adenocarcinomas, followed by adenomas and fibroadenomas. The incidence and multiplicity (mean ± standard deviation) of mammary adenocarcinomas induced by these twocarcinogens at the highest dose (6-NC: 90%, 3.73 ± 2.74; PhIP: 83%, 2.62 ± 2.58) weresignificantly higher than those in control rats (10%, 0.10 ± 0.31). However, there were nostatistically significant differences between groups treated with 6-NC and PhIP or among groupsreceiving various doses of 6-NC. Following its metabolic activation, 6-NC is known to bindcovalently to DNA; however, it remains to be determined whether it can also induce DNAbase oxidation. Thus, employing the same route of administration, our studies revealed noeffect of 6-NC on the basal level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the mammarygland in tests at 6, 24, and 48 h after 6-NC treatment and at termination of the carcinogenesisassay in the normal, noninvolved tissue and in mammary tumors. This result suggests thatcovalent DNA binding of 6-NC metabolites is important in the induction of mammary cancerin rats. Therefore, the other goal of this study was to compare the tumorigenic activities of6-NC and its metabolites in the rat mammary gland by intramammary administration. Thisroute has also been used in our laboratory to induce mammary cancer in the rat by 6-NC andis employed here to avoid systemic effects and to determine the role of the mammary gland inthe metabolic activation of 6-NC and its metabolites. Toward this end, a new method wasdeveloped to obtain ample materials of trans-1,2-dihydroxy-1,2-dihydro-6-aminochrysene (1,2-DHD-6-AC); other metabolites were synthesized as reported previously. On the basis of theresults, the carcinogenic potency toward the mammary gland is ranked in the following order:6-NC > 1,2-DHD-6-NC > 6-AC > 6-NCDE > 1,2-DHD-6-AC. Among the metabolites tested,1,2-DHD-6-NC was the most potent carcinogen. It was significantly more active than its reducedproduct 1,2-DHD-6-AC. However, the potency of 1,2-DHD-6-NC was not significantly differentfrom 6-AC, a metabolite derived from simple nitroreduction, or from 6-NCDE. Collectively,these results suggest that metabolites derived from both ring-oxidation and nitroreductioncontribute to the overall carcinogenicity of 6-NC in the rat mammary gland.
mol/rat or PhIP at 50 mol/rat in 500L of trioctanoin. Twenty-three weeks after the last carcinogen administration, rats weredecapitated, necropsied, and evaluated histologically. The most common mammary tumorswere adenocarcinomas, followed by adenomas and fibroadenomas. The incidence and multiplicity (mean ± standard deviation) of mammary adenocarcinomas induced by these twocarcinogens at the highest dose (6-NC: 90%, 3.73 ± 2.74; PhIP: 83%, 2.62 ± 2.58) weresignificantly higher than those in control rats (10%, 0.10 ± 0.31). However, there were nostatistically significant differences between groups treated with 6-NC and PhIP or among groupsreceiving various doses of 6-NC. Following its metabolic activation, 6-NC is known to bindcovalently to DNA; however, it remains to be determined whether it can also induce DNAbase oxidation. Thus, employing the same route of administration, our studies revealed noeffect of 6-NC on the basal level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the mammarygland in tests at 6, 24, and 48 h after 6-NC treatment and at termination of the carcinogenesisassay in the normal, noninvolved tissue and in mammary tumors. This result suggests thatcovalent DNA binding of 6-NC metabolites is important in the induction of mammary cancerin rats. Therefore, the other goal of this study was to compare the tumorigenic activities of6-NC and its metabolites in the rat mammary gland by intramammary administration. Thisroute has also been used in our laboratory to induce mammary cancer in the rat by 6-NC andis employed here to avoid systemic effects and to determine the role of the mammary gland inthe metabolic activation of 6-NC and its metabolites. Toward this end, a new method wasdeveloped to obtain ample materials of trans-1,2-dihydroxy-1,2-dihydro-6-aminochrysene (1,2-DHD-6-AC); other metabolites were synthesized as reported previously. On the basis of theresults, the carcinogenic potency toward the mammary gland is ranked in the following order:6-NC > 1,2-DHD-6-NC > 6-AC > 6-NCDE > 1,2-DHD-6-AC. Among the metabolites tested,1,2-DHD-6-NC was the most potent carcinogen. It was significantly more active than its reducedproduct 1,2-DHD-6-AC. However, the potency of 1,2-DHD-6-NC was not significantly differentfrom 6-AC, a metabolite derived from simple nitroreduction, or from 6-NCDE. Collectively,these results suggest that metabolites derived from both ring-oxidation and nitroreductioncontribute to the overall carcinogenicity of 6-NC in the rat mammary gland.