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7 pages, 453 KiB

Open AccessCommunication

Considerations for Applying Route-to-Route Extrapolation to Assess the Safety of Oral Exposure to Substances

by Shruti V. Kabadi, Jeffrey Fisher, Benjamin Hung and Jason Aungst

Biomolecules 2023, 13(1), 5; https://doi.org/10.3390/biom13010005 - 20 Dec 2022

Viewed by 1369

Abstract

The safety evaluation of oral exposure to substances, such as food ingredients, additives, and their constituents, relies primarily on a careful evaluation and analysis of data from oral toxicity studies. When relevant oral toxicity studies are unavailable or may have significant data gaps [...] Read more.

The safety evaluation of oral exposure to substances, such as food ingredients, additives, and their constituents, relies primarily on a careful evaluation and analysis of data from oral toxicity studies. When relevant oral toxicity studies are unavailable or may have significant data gaps that make them inadequate for use in safety evaluations, data from non-oral toxicity studies in animals, such as studies on inhalation, dermal exposure, etc., might be used in support of or in place of oral toxicity studies through route-to-route (R-t-R) extrapolation. R-t-R extrapolation is applied on a case-by-case basis as it requires attention to and comparison of substance-specific toxicokinetic (TK) and toxicodynamic (TD) data for oral and non-oral exposure routes. This article provides a commentary on the utility of R-t-R extrapolation to assess the safety of oral exposure to substances, with an emphasis on the relevance of TK and systemic toxicity data. Full article

(This article belongs to the Special Issue Pharmacokinetics, Pharmacodynamics, and Toxicology of Small-Molecule Drugs and Nanomedicine)

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24 pages, 9223 KiB

Open AccessArticle

Toxicity Assessment of an Anti-Cancer Drug of p-Toluene Sulfonamide in Zebrafish Larvae Based on Cardiovascular and Locomotion Activities

by Andrew Yau Wah Young, Gilbert Audira, Ferry Saputra, Honeymae C. Alos, Charlaine A. Aventurado, Yu-Heng Lai, Ross D. Vasquez, Chung-Der Hsiao and Chih-Hsin Hung

Biomolecules 2022, 12(8), 1103; https://doi.org/10.3390/biom12081103 - 10 Aug 2022

Cited by 5 | Viewed by 2485

Abstract

p-Toluene sulfonamide (p-TSA), a small molecular drug with antineoplastic activity is widely gaining interest from researchers because of its pharmacological activities. In this study, we explored the potential cardio and neural toxicity of p-TSA in sublethal concentrations by using zebrafish as an in [...] Read more.

p-Toluene sulfonamide (p-TSA), a small molecular drug with antineoplastic activity is widely gaining interest from researchers because of its pharmacological activities. In this study, we explored the potential cardio and neural toxicity of p-TSA in sublethal concentrations by using zebrafish as an in vivo animal model. Based on the acute toxicity assay, the 96hr LC₅₀ was estimated as 204.3 ppm, suggesting the overall toxicity of p-TSA is relatively low in zebrafish larvae. For the cardiotoxicity test, we found that p-TSA caused only a minor alteration in treated larvae after no overall significant alterations were observed in cardiac rhythm and cardiac physiology parameters, as supported by the results from expression level measurements of several cardiac development marker genes. On the other hand, we found that acute p-TSA exposure significantly increased the larval locomotion activity during the photomotor test while prolonged exposure (4 days) reduced the locomotor startle reflex activities in zebrafish. In addition, a higher respiratory rate and blood flow velocity was also observed in the acutely treated fish groups compared to the untreated group. Finally, by molecular docking, we found that p-TSA has a moderate binding affinity to skeletal muscle myosin II subfragment 1 (S1), ATPase activity, actin- and Ca²⁺-stimulated myosin S1 ATPase, and v-type proton ATPase. These binding interactions between p-TSA and proteins offer insights into the potential molecular mechanism of action of p-TSA on observed altered responses toward photo and vibration stimuli and minor altered vascular performance in the zebrafish larvae. Full article

(This article belongs to the Special Issue Pharmacokinetics, Pharmacodynamics, and Toxicology of Small-Molecule Drugs and Nanomedicine)

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Review

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16 pages, 3480 KiB

Open AccessReview

Small-Molecule Inhibitors Targeting FEN1 for Cancer Therapy

by Fan Yang, Zhigang Hu and Zhigang Guo

Biomolecules 2022, 12(7), 1007; https://doi.org/10.3390/biom12071007 - 20 Jul 2022

Cited by 19 | Viewed by 4231

Abstract

DNA damage repair plays a key role in maintaining genomic stability and integrity. Flap endonuclease 1 (FEN1) is a core protein in the base excision repair (BER) pathway and participates in Okazaki fragment maturation during DNA replication. Several studies have implicated FEN1 in [...] Read more.

DNA damage repair plays a key role in maintaining genomic stability and integrity. Flap endonuclease 1 (FEN1) is a core protein in the base excision repair (BER) pathway and participates in Okazaki fragment maturation during DNA replication. Several studies have implicated FEN1 in the regulation of other DNA repair pathways, including homologous recombination repair (HRR) and non-homologous end joining (NHEJ). Abnormal expression or mutation of FEN1 in cells can cause a series of pathological responses, leading to various diseases, including cancers. Moreover, overexpression of FEN1 contributes to drug resistance in several types of cancers. All this supports the hypothesis that FEN1 could be a therapeutic target for cancer treatment. Targeting FEN1 has been verified as an effective strategy in mono or combined treatment of cancer. Small-molecule compounds targeting FEN1 have also been developed and detected in cancer regression. In this review, we summarize the recent development of small-molecule inhibitors targeting FEN1 in recent years, thereby expanding their therapeutic potential and application. Full article

(This article belongs to the Special Issue Pharmacokinetics, Pharmacodynamics, and Toxicology of Small-Molecule Drugs and Nanomedicine)

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