Approaches for Identification and Validation of Antimicrobial Compounds of Plant Origin: A Long Way from the Field to the Market
Mahendra Rai, Chistiane M. Feitosa in Eco-Friendly Biobased Products Used in Microbial Diseases, 2022
For the detection of the in vitro limit cytotoxic concentration, one out of four cytogenetic tests (RICC, RPD, CBPI or RI) with sufficient compound concentration to induce cytotoxicity is recommended by ICH and OECD (OECD 2016a). However, there are divergences in the selection of the maximum concentration used for in vitro tests. FDA and EMA S2 (R1) guides recommend maximum concentrations of 1 mM or 500 µg/mL (Kirkland and Fowler 2010), while OECD TGs 487 and 473 recommend 10 mM or 5000 µg/mL. Additionally, in some cases, as plant extracts, the composition of the tested substance is not well defined (OECD 2016a). On the other hand, all guides recommend that genotoxic analysis use concentrations that do not exceed 50% cytotoxicity (FDA 2012; OECD 2016a; OECD 2016b).
Chemical Carcinogenesis and Mutagenesis
Frank A. Barile in Barile’s Clinical Toxicology, 2019
The carcinogenic process is, on occasion, a response to a mutation occurring within the genetic material of normal cells, resulting in uncontrolled cell division and transformation to the immortal phenotype. The unrestrained and often rapid proliferation of cells is further characterized as benign or malignant. Benign tumors do not metastasize, are usually confined to local target organ areas, are clinically susceptible to therapeutic intervention, and carry a more favorable prognosis. Alternatively, malignant tumors metastasize to distant organ locations, are not necessarily amenable to therapeutic intervention, and possess a less favorable prognosis. Mutagenesis refers to the ability of a virus or chemical agent to induce changes in the genetic sequence of mammalian or bacterial cells, thus altering the phenotypic expression of cell characteristics. Genotoxicity refers to the ability of an agent to induce heritable changes in genes that exercise homeostatic control in somatic cells while increasing the risk of influencing benign or malignant transformation. Genotoxic substances induce genotoxicity either by binding directly to DNA or by indirectly altering the DNA sequence, resulting in irreversible damage. It is also important to note, however, that genotoxic substances are not necessarily carcinogenic.
Toxicogenomics in Toxicologic Pathology
Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard in Toxicologic Pathology, 2018
Genotoxic mechanisms of direct DNA damage are a hallmark of carcinogenesis. Prediction of carcinogenicity of compounds in vitro, using standard genotoxicity assays, is the current standard by which prediction of genotoxic mechanisms is measured. However, current assays that are used to detect genotoxicity are somewhat imprecise, have low specificity, and are generally insufficient to model the complex disease of cancer, and can often over-predict carcinogenesis, leading to false-positive results (Ellinger-Ziegelbauer et al. 2008, 2009; Kirkland et al. 2005; Kirkland et al. 2006; Ward 2007). In addition, over ½ of chemically induced tumors are caused by non-genotoxic compounds, which are difficult to predict in short-term assays (Nie et al. 2006). Furthermore, non-genotoxic compounds may induce a genotoxic response in vitro using current genotoxicity assays, due to secondary mechanisms of DNA damage, as discussed previously. This makes interpretation of genotoxicity data for non-genotoxic compounds confusing and difficult in terms of human risk assessment. In fact, the ability to predict carcinogenicity in humans as a result of these assays has been questioned (Ellinger-Ziegelbauer et al. 2009; Kirkland et al. 2006; Waters et al. 2010). Additionally, since non-genotoxic mechanisms may be dictated or influenced by a dose response and be subject to a no adverse effect level (NOAEL), both the assessment of mechanism as well as prediction of carcinogenesis based on dose response, are important for non-genotoxic compounds relative to risk assessment.
Is a non-cytotoxic and non-genotoxic novel bioinspired dipeptide structure synthesis possible for theragnostic applications?
Published in Drug and Chemical Toxicology, 2023
Merve Bacanlı, Jülide Secerli, Burcu Karayavuz, Onur Erdem, Hakan Erdoğan
It is also important to investigate the genotoxic effects in evaluation of the toxic effects of the theragnostics synthesized with new approaches. Genotoxicity can cause irreversible damage to DNA, mutagenicity, and cancer formation. There are several assays available that can be used to detect genotoxicity. One of the most common DNA damage assays is the single-cell gel electrophoresis assay, commonly known as the Comet assay (Catalán etal.2014). The results of the genotoxic effects of Hg2+/Phe–Phe dipeptides in NIH/3T3 cells by the alkaline Comet assay are shown in Figure 5. At 4- and 24-h exposures, Hg2+/Phe–Phe dipeptides did not cause any significant changes in DNA damage in NIH/3T3 cells at concentrations of 1, 2, and 5 mg/mL. At the 48-h exposure, Hg2+/Phe–Phe dipeptide exposure at concentrations of 2 and 5 mg/mL caused a significant increase in DNA damage compared to the negative control. At 72 h of exposure, a significant increase in DNA damage was observed in NIH/3T3 cells compared to the negative control at all concentrations.
Cationic nanocapsule suspension as an alternative to the sublingual delivery of nifedipine
Published in Pharmaceutical Development and Technology, 2023
Bárbara Felin Osmari, Giovana Aime Medeiros, Jéssica Brandão Reolon, Vinícius Costa Prado, Natália Brucker, Letícia Cruz
Genotoxic substances can break genetic material, causing abnormal changes in genes or chromosomes structure (Islam etal. 2017). The genotoxicity was evaluated by observing chromosomal aberrations (CA%) (Table 3). The evaluations confirmed the genotoxicity of glyphosate (positive control) that presented CA of 1.07 ± 0.17%. On the other hand, the negative control group treated with water presented CA of 0.24 ± 0.06%, being similar to NC-NIFE (0.14 ± 0.10%), NC (0.19 ± 0.09%), and vehicle (0.16 ± 0.14%) (p > 0.05). Interestingly, NIFE showed the lowest CA (0.07 ± 0.10%). In Figure 3(B), the images of CA observed in this study are shown. The different mitosis phases are shown in Figure 3(A). Thus, NC-NIFE demonstrated the absence of chromosomic aberrations, which was also observed in other nanoencapsulated drugs (Marchiori etal. 2010; Leng etal. 2018).
Genotoxic and mutagenic potential of 7-methylxanthine: an investigational drug molecule for the treatment of myopia
Published in Drug and Chemical Toxicology, 2023
Harjeet Singh, Harmanpreet Singh, Sunil Sharma, Harmanpreet Kaur, Arvinder Kaur, Satwinderjeet Kaur, Sandeep Kaur, Nikhil Shri Sahajpal, Alka Chaubey, Navid Reza Shahtaghi, Inderjeet Kaur, Subheet Kumar Jain
Treatment of myopia requires prolonged medication. Starting from the age of 6 up to the age of 18. Therefore, an ideal drug candidate should have no or minimal toxicity, non-mutagenic characteristics, and no cumulative organ toxicity. The approval and registration of drugs therefore need a comprehensive assessment of the genotoxic/mutagenic nature of the new drug under investigation. Thus, genotoxicity serves as a vital component of regulatory toxicity determination in various countries. Any single test is not capable of detecting all the relevant information about genotoxicity for a new drug molecule. Therefore, a series of various in-vivo and in-vitro tests are required to assess genotoxicity. The standard tests recommended by the regulatory agencies include the Ames test, in-vivo assays to detect gene mutations using single-cell gel electrophoresis for single-or double-strand DNA breaks, the micronucleus test, and chromosomal aberration in mammalian cells (Savale, 2018).
