Structure, Tumorigenicity, Microsomal Metabolism, and DNA Binding of 7-Nitrodibenz[a,h]anthracene
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- 作者：Peter P. Fu ; Linda S. Von Tungeln ; Li-Hsueh Chiu ; De-Jin Zhan ; Joanna Deck ; Thomas Bucci ; and Ju-Chun Wang
- 刊名：Chemical Research in Toxicology
- 出版年：1998
- 出版时间：August 1998
- 年：1998
- 卷：11
- 期：8
- 页码：937 - 945
- 全文大小：128K
- 年卷期：v.11,no.8(August 1998)
- ISSN：1520-5010
文摘
It has been previously proposed that a nitropolycyclic aromatic hydrocarbon (nitro-PAH)with its nitro functional group perpendicular or nearly perpendicular to the aromatic moietyexhibits lower tumorigenicity than the corresponding parent aromatic hydrocarbon. We alsohypothesized that reduction of the nitro group is not involved, or contributed less significantlyin the metabolic activation of this class of nitro-PAHs. To verify this hypothesis, we selected7-nitrodibenz[a,h]anthracene (7-NDB[a,h]A) for study. The X-ray crystallographic structureof 7-NDB[a,h]A was determined and indicated that the dihedral angle between the nitrofunctional group and the aromatic dibenz[a,h]anthracenyl moiety was 80.6
, indicating thenitro group preferentially adopts a nearly perpendicular orientation. The tumorigenicity of7-NDB[a,h]A and dibenz[a,h]anthracene (DB[a,h]A) was determined in the male B6C3F1neonatal mouse. Mice were administered ip injections of 1/7, 2/7, and 4/7 of the total dose of7-NDB[a,h]A (400 nmol in 35 
L of DMSO per mouse) within 24 h of birth and at 8 and 15days of age, respectively, and sacrificed at 12 months of age. DB[a,h]A induced 78 and 96%hepatocellular adenomas and carcinomas, respectively. However, 7-NDB[a,h]A induced only50 and 8% hepatocellular adenomas and carcinomas compared with the 8 and 4% hepatocellularadenomas and carcinomas induced by the solvent vehicle, DMSO. Aerobic metabolism of7-NDB[a,h]A by liver microsomes of 15-day old male B6C3F1 neonatal mice resulted in trans-3,4-dihydroxy-3,4-dihydro-7-nitrodibenz[a,h]anthracene (7-NDB[a,h]A trans-3,4-dihydrodiol)and trans-10,11-dihydroxy-10,11-dihydro-7-nitrodibenz[a,h]anthracene (7-NDB[a,h]A trans-10,11-dihydrodiol) as predominant metabolites. Under anaerobic conditions, 7-NDB[a,h]A wasnot metabolized (nitroreduced). The DNA adduct levels in liver and lung tissues of male B6C3F1mice treated with 7-NDB[a,h]A and sacrificed 24 h and 6 days after final dosing weredetermined by 32P-postlabeling/TLC. In all cases, the DNA adducts derived from 7-NDB[a,h]Atrans-3,4-dihydrodiol and 7-NDB[a,h]A trans-10,11-dihydrodiol were formed. These resultssuggest that both of the metabolites, 7-NDB[a,h]A trans-3,4-dihydrodiol and 7-NDB[a,h]A trans-10,11-dihydrodiol, are involved in the metabolic activation of 7-NDB[a,h]A, leading to tumorinduction in the neonatal mouse. Thus, our results described in this paper support ourhypotheses that a nitro-PAH with a perpendicular nitro orientation exhibits lower tumorigenicity than the corresponding parent PAH and that nitroreduction contributes less significantlyin the metabolic activation.
, indicating thenitro group preferentially adopts a nearly perpendicular orientation. The tumorigenicity of7-NDB[a,h]A and dibenz[a,h]anthracene (DB[a,h]A) was determined in the male B6C3F1neonatal mouse. Mice were administered ip injections of 1/7, 2/7, and 4/7 of the total dose of7-NDB[a,h]A (400 nmol in 35 L of DMSO per mouse) within 24 h of birth and at 8 and 15days of age, respectively, and sacrificed at 12 months of age. DB[a,h]A induced 78 and 96%hepatocellular adenomas and carcinomas, respectively. However, 7-NDB[a,h]A induced only50 and 8% hepatocellular adenomas and carcinomas compared with the 8 and 4% hepatocellularadenomas and carcinomas induced by the solvent vehicle, DMSO. Aerobic metabolism of7-NDB[a,h]A by liver microsomes of 15-day old male B6C3F1 neonatal mice resulted in trans-3,4-dihydroxy-3,4-dihydro-7-nitrodibenz[a,h]anthracene (7-NDB[a,h]A trans-3,4-dihydrodiol)and trans-10,11-dihydroxy-10,11-dihydro-7-nitrodibenz[a,h]anthracene (7-NDB[a,h]A trans-10,11-dihydrodiol) as predominant metabolites. Under anaerobic conditions, 7-NDB[a,h]A wasnot metabolized (nitroreduced). The DNA adduct levels in liver and lung tissues of male B6C3F1mice treated with 7-NDB[a,h]A and sacrificed 24 h and 6 days after final dosing weredetermined by 32P-postlabeling/TLC. In all cases, the DNA adducts derived from 7-NDB[a,h]Atrans-3,4-dihydrodiol and 7-NDB[a,h]A trans-10,11-dihydrodiol were formed. These resultssuggest that both of the metabolites, 7-NDB[a,h]A trans-3,4-dihydrodiol and 7-NDB[a,h]A trans-10,11-dihydrodiol, are involved in the metabolic activation of 7-NDB[a,h]A, leading to tumorinduction in the neonatal mouse. Thus, our results described in this paper support ourhypotheses that a nitro-PAH with a perpendicular nitro orientation exhibits lower tumorigenicity than the corresponding parent PAH and that nitroreduction contributes less significantlyin the metabolic activation.