Abstract 4795: N-hydroxylation of 4-aminobiphenyl (ABP) and associated oxidative stress may influence ABP carcinogenicity in the mouse liver.
Bibliographic record
Abstract
Abstract Liver cancer is the 3rd most common cause of death from cancer worldwide due to poor prognosis and lack of treatment options. A prominent sex difference is observed in human liver cancer such that men have a 3 to 5 fold higher incidence than women even after accounting for known etiological factors. In a tumor study carried out previously in our laboratory, two doses of the human carcinogen 4-aminobiphenyl (ABP) given to mice on postnatal days 8 and 15 resulted in the formation of liver tumors at 1 year. Moreover, female mice were dramatically protected from liver tumors compared to males, which parallels the sex difference found in human liver cancer. Our goal is to elucidate the molecular mechanisms behind the sex differences in ABP carcinogenesis in mouse liver with the hope of extrapolating to the human condition. Oxidative stress may play an important role in human liver carcinogenesis since all major etiological factors for human liver cancer, including viral hepatitis, alcohol, obesity and chemical carcinogens have been shown to be associated with oxidative stress. To determine whether oxidative stress is involved in ABP-mediated carcinogenesis in the mouse, we first assessed the ability of ABP to generate oxidative stress in the mouse Hepa1c1c7 hepatoma cell line. ABP did not produce reactive oxygen species (ROS) or oxidative DNA damage in Hepa1c1c7 cells. However, N-hydroxy-ABP (HOABP), an in vivo metabolite of ABP, was a potent inducer of both ROS and oxidative DNA damage. Furthermore, HOABP-induced oxidative stress was dose-dependent and could be blocked by co-treatment with the antioxidant N-acetylcysteine. These results suggest that HOABP may be a potential source of oxidative stress in mouse liver. We subsequently characterized the kinetics of ABP N-hydroxylation by mouse liver microsomes, and found that more than one cytochrome P450 (CYP) appears to be involved in the reaction. As predicted by the traditional model of ABP bioactivation, the high affinity ABP N-hydroxylation reaction is mediated by CYP1A2, while at least one additional low affinity site belonging to an as yet unidentified CYP is responsible for significant ABP N-hydroxylation at higher concentrations of ABP that would be expected following the doses of ABP used in our tumor study. However, no sex difference was found in either high or low affinity ABP N-hydroxylation activities between liver microsomes from male and female postnatal (day 15) or adult mice. Future studies will focus on quantifying both acute and chronic changes in oxidative stress and antioxidant levels in the mouse liver following carcinogenic doses of ABP, and correlating such changes to tumor formation. Citation Format: Shuang Wang, Kim S. Sugamori, Denis M. Grant. N-hydroxylation of 4-aminobiphenyl (ABP) and associated oxidative stress may influence ABP carcinogenicity in the mouse liver. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4795. doi:10.1158/1538-7445.AM2013-4795
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".