Abstract 4795: N-hydroxylation of 4-aminobiphenyl (ABP) and associated oxidative stress may influence ABP carcinogenicity in the mouse liver.
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,001 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».