AhR Activation in Pharmaceutical Development: Applying Liver Gene Expression Biomarker Thresholds to Identify Doses Associated With Tumorigenic Risks in Rats
| Autor: | Todd Pippert, Amy G Aslamkhan, Keith Q. Tanis, Stephen Pacchione, Chunhua Qin, Warren E. Glaab, Alexei A. Podtelezhnikov, Frank D. Sistare, Kara Pearson, Erika Frank |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Drug biology business.industry media_common.quotation_subject CYP1A2 respiratory system Pharmacology Toxicology Aryl hydrocarbon receptor respiratory tract diseases 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Drug development Toxicity Gene expression biology.protein Medicine Biomarker (medicine) business 030217 neurology & neurosurgery Carcinogen media_common |
| Zdroj: | Toxicological Sciences. 171:46-55 |
| ISSN: | 1096-0929 1096-6080 |
| Popis: | Aryl hydrocarbon receptor (AhR) activation is associated with carcinogenicity of non-genotoxic AhR-activating carcinogens such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD), and is often observed with drug candidate molecules in development and raises safety concerns. As downstream effectors of AhR signaling, the expression and activity of Cyp1a1 and Cyp1a2 genes are commonly monitored as evidence of AhR activation to inform carcinogenic risk of compounds in question. However, many marketed drugs and phytochemicals are reported to induce these Cyps modestly and are not associated with dioxin-like toxicity or carcinogenicity. We hypothesized that a threshold of AhR activation needs to be surpassed in a sustained manner in order for the dioxin-like toxicity to manifest, and a simple liver gene expression signature based on Cyp1a1 and Cyp1a2 from a short-term rat study could be used to assess AhR activation strength and differentiate tumorigenic dose levels from non-tumorigenic ones. To test this hypothesis, short-term studies were conducted in Wistar Han rats with 2 AhR-activating carcinogens (TCDD and PCB126) at minimally carcinogenic and noncarcinogenic dose levels, and 3 AhR-activating noncarcinogens (omeprazole, mexiletine, and canagliflozin) at the top doses used in their reported 2-year rat carcinogenicity studies. A threshold of AhR activation was identified in rat liver that separated a meaningful “tumorigenic-strength AhR signal” from a statistically significant AhR activation signal that was not associated with dioxin-like carcinogenicity. These studies also confirmed the importance of the sustainability of AhR activation for carcinogenic potential. A sustained activation of AhR above the threshold could thus be used in early pharmaceutical development to identify dose levels of drug candidates expected to exhibit dioxin-like carcinogenic potential. |
| Databáze: | OpenAIRE |
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