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Utility of Physicochemical Properties for the Prediction of Toxicological Outcomes: Takeda Perspective.

ABSTRACT: The role that physicochemical properties play toward increasing the likelihood of toxicity findings in in vivo studies has been well reported, albeit sometimes with different conclusions. We decided to understand the role that physicochemical properties play toward the prediction of in vivo toxicological outcomes for Takeda chemistry using 284 internal compounds. In support of the previously reported "3/75 rule", reducing lipophilicity of molecules decreases toxicity odds noticeably; however, we also found that the trend of toxicity odds is different between compounds classified by their ionization state. For basic molecules, the odds of in vivo toxicity outcomes were significantly impacted by both lipophilicity and polar surface area, whereas neutral molecules were impacted less so. Through an analysis of several project-related compounds, we herein demonstrate that the utilization of the 3/75 rule coupled with consideration of ionization state is a rational strategy for medicinal chemistry design of safer drugs.

SUBMITTER: Yukawa T

PROVIDER: S-EPMC7025387 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Utility of Physicochemical Properties for the Prediction of Toxicological Outcomes: Takeda Perspective.

Yukawa Tomoya T Naven Russell R

ACS medicinal chemistry letters 20200129 2

The role that physicochemical properties play toward increasing the likelihood of toxicity findings in <i>in vivo</i> studies has been well reported, albeit sometimes with different conclusions. We decided to understand the role that physicochemical properties play toward the prediction of <i>in vivo</i> toxicological outcomes for Takeda chemistry using 284 internal compounds. In support of the previously reported "3/75 rule", reducing lipophilicity of molecules decreases toxicity odds noticeabl ...[more]

PMID: 32071689

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Project description:Purpose: In the last decades, the advancements of nanotechnologies lead to a massive increase of engineered nanoparticles in consumer products, which translates in an increased human and environmental exposure to nanomaterials. For humans, inhalation is considered as the main exposure route to nanomaterials, which is the reason why lung toxicity studies should be considered as a priority. Inhalation studies are often performed in vivo in rodents. Therefore, in vitro models may represent a valid and efficient alternative to predict the acute toxicity effects of inhaled NPs on human health. The model used in this study represents the human alveolar barrier; it is constituted by four different human pulmonary cell lines (EA.hy 296 on the basolateral side; A549, HMC-1 and macrophage-like cells in the apical side). The cells in the apical side were cultivated at the air-liquid-interface (ALI) and they have been exposed to AuNPs with the VitroCell® Cloud System. Results: We describe the effects after 24 hours of exposure to three different gold nanoparticles (AuNPs) in order to evaluate the suitability of our model to assess the toxicological effects of particles. The set of PEGylated AuNPs used included spheres (GNPs), rods (GNRs) and stars (GNSs). The exposure did not cause any significant decrease of viability; all the AuNPs caused cytotoxicity and increase of IL-8 levels at the highest dose. The AuNP were up-taken by the cells in the apical side and they also translocated in the basolateral side. Regarding the global transcript, among differentially expressed genes (DEG) were found genes related to the enhancement of immune cells. Conclusion: AuNPs in the used range of concentrations did not cause severe effects on the co-culture, but different effects were observed for the different types of AuNPs supporting the role of the physico-chemical NP parameters in NP-cell interactions. In addition, our model resulted perfectly suitable to investigate the biological effects of particles especially in terms of inflammatory response and translocation.

Project description:The physicochemical properties of combustion particles that promote lung toxicity are not fully understood, hindered by the fact that combustion particles vary based on the fuel and combustion conditions. Real-world combustion-particle properties also continually change as new fuels are implemented, engines age, and engine technologies evolve. This work used laboratory-generated particles produced under controlled combustion conditions in an effort to understand the relationship between different particle properties and the activation of established toxicological outcomes in human lung cells (H441 and THP-1). Particles were generated from controlled combustion of two simple biofuel/diesel surrogates (methyl decanoate and dodecane/biofuel-blended diesel (BD), and butanol and dodecane/alcohol-blended diesel (AD)) and compared to a widely studied reference diesel (RD) particle (NIST SRM2975/RD). BD, AD, and RD particles exhibited differences in size, surface area, extractable chemical mass, and the content of individual polycyclic aromatic hydrocarbons (PAHs). Some of these differences were directly associated with different effects on biological responses. BD particles had the greatest surface area, amount of extractable material, and oxidizing potential. These particles and extracts induced cytochrome P450 1A1 and 1B1 enzyme mRNA in lung cells. AD particles and extracts had the greatest total PAH content and also caused CYP1A1 and 1B1 mRNA induction. The RD extract contained the highest relative concentration of 2-ring PAHs and stimulated the greatest level of interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNFα) cytokine secretion. Finally, AD and RD were more potent activators of TRPA1 than BD, and while neither the TRPA1 antagonist HC-030031 nor the antioxidant N-acetylcysteine (NAC) affected CYP1A1 or 1B1 mRNA induction, both inhibitors reduced IL-8 secretion and mRNA induction. These results highlight that differences in fuel and combustion conditions affect the physicochemical properties of particles, and these differences, in turn, affect commonly studied biological/toxicological responses.

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Utility of Physicochemical Properties for the Prediction of Toxicological Outcomes: Takeda Perspective.

Publications

Utility of Physicochemical Properties for the Prediction of Toxicological Outcomes: Takeda Perspective.

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