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Journal of Medicinal Chemistry Jul 2023Phototoxicity is a common safety concern encountered by project teams in pharmaceutical research and has the potential to stop progression of an otherwise promising... (Review)
Review
Phototoxicity is a common safety concern encountered by project teams in pharmaceutical research and has the potential to stop progression of an otherwise promising candidate molecule. This perspective aims to provide an overview of the approaches toward mitigation of phototoxicity that medicinal chemists have taken during the lead optimization phase in the context of regulatory standards for photosafety evaluation. Various strategies are laid out based on available literature examples in order to highlight how structural modification can be utilized toward successful mitigation of a phototoxicity liability. A proposed flowchart is presented as a guidance tool to be used by the practicing medicinal chemist when facing a phototoxicity risk. The description of available tools to consider in the drug design process will include an overview of the evolution of in silico methods and their application as well as structure alerts for consideration as potential phototoxicophores.
Topics: Humans; Drug Discovery; Drug Design; Dermatitis, Phototoxic; Chemistry, Pharmaceutical
PubMed: 37450689
DOI: 10.1021/acs.jmedchem.3c00749 -
Molecules (Basel, Switzerland) Aug 2023Indocyanine green (ICG) is an important kind of near infrared (NIR) photosensitive molecules for PTT/PDT therapy as well as imaging. When exposed to NIR light, ICG can... (Review)
Review
Indocyanine green (ICG) is an important kind of near infrared (NIR) photosensitive molecules for PTT/PDT therapy as well as imaging. When exposed to NIR light, ICG can produce reactive oxygen species (ROS), which can kill cancer cells and pathogenic bacteria. Moreover, the absorbed light can also be converted into heat by ICG molecules to eliminate cancer cells. In addition, it performs exceptionally well in optical imaging-guided tumor therapy and antimicrobial therapy due to its deeper tissue penetration and low photobleaching properties in the near-infrared region compared to other dyes. In order to solve the problems of water and optical stability and multi-function problem of ICG molecules, composite nanomaterials based on ICG have been designed and widely used, especially in the fields of tumors and sterilization. So far, ICG molecules and their composite materials have become one of the most famous infrared sensitive materials. However, there have been no corresponding review articles focused on ICG molecules. In this review, the molecular structure and properties of ICG, composite material design, and near-infrared light- triggered anti-tumor, and antibacterial, and clinical applications are reviewed in detail, which of great significance for related research.
Topics: Humans; Indocyanine Green; Dermatitis, Phototoxic; Coloring Agents; Anti-Bacterial Agents; Hot Temperature
PubMed: 37630337
DOI: 10.3390/molecules28166085 -
Journal of Radiation Research Mar 2015Histone H2AX is a minor component of nuclear histone H2A. The phosphorylation of histone H2AX at Ser 139, termed γ-H2AX, was originally identified as an early event... (Review)
Review
Histone H2AX is a minor component of nuclear histone H2A. The phosphorylation of histone H2AX at Ser 139, termed γ-H2AX, was originally identified as an early event after the direct formation of DNA double-strand breaks (DSBs) by ionizing radiation. Now, the generation of γ-H2AX is also considered to occur in association with secondarily formed DSBs by cellular processing such as DNA replication and repair at the site of the initial damage, including DNA adducts, crosslinks, and UV-induced photolesions. Therefore, γ-H2AX is currently attracting attention as a new biomarker for detecting various genotoxic insults. We have determined the toxic impact of various environmental stresses such as chemicals, light and/or their coexposure using γ-H2AX, and found that the γ-H2AX assay exhibited high sensitivity and a low false-positive rate as a detection system of genotoxic potential. In this review, we introduced our recent findings concerning the evaluation of chemical phototoxicity, focusing on γ-H2AX.
Topics: Animals; DNA Damage; DNA Repair; Dermatitis, Phototoxic; Histones; Humans; Mutagenicity Tests; Phosphorylation
PubMed: 25480829
DOI: 10.1093/jrr/rru105 -
RIFM fragrance ingredient safety assessment, phenylethyl anthranilate, CAS Registry Number 133-18-6.Food and Chemical Toxicology : An... Oct 2020The existing information supports the use of this material as described in this safety assessment. Phenylethyl anthranilate was evaluated for genotoxicity, repeated dose... (Review)
Review
The existing information supports the use of this material as described in this safety assessment. Phenylethyl anthranilate was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from phenylethyl anthranilate and the read-across analog cinnamyl anthranilate (CAS # 87-29-6) show that phenylethyl anthranilate is not expected to be genotoxic. The skin sensitization endpoint was completed using the DST for non-reactive materials (900 μg/cm); exposure is below the DST. The reproductive and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class II material, and the exposure to phenylethyl anthranilate is below the TTC (0.009 mg/kg/day and 0.47 mg/day, respectively). Data on read-across analogs phenethyl alcohol (CAS # 60-12-8) and anthranilic acid (CAS # 118-92-3) provide a calculated MOE >100 for the repeated dose and developmental toxicity endpoints. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; phenylethyl anthranilate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; phenylethyl anthranilate was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.
Topics: Animals; Dermatitis, Phototoxic; Humans; Mutagenicity Tests; Perfume; Registries; Risk Assessment; ortho-Aminobenzoates
PubMed: 32640364
DOI: 10.1016/j.fct.2020.111470 -
Molecules (Basel, Switzerland) Dec 2021Polyphenols are a large family of natural compounds widely used in cosmetic products due to their antioxidant and anti-inflammatory beneficial properties and their...
Polyphenols are a large family of natural compounds widely used in cosmetic products due to their antioxidant and anti-inflammatory beneficial properties and their ability to prevent UV radiation-induced oxidative stress. Since these compounds present chromophores and are applied directly to the skin, they can react with sunlight and exert phototoxic effects. The available scientific information on the phototoxic potential of these natural compounds is scarce, and thus the aim of this study was to evaluate the photoreactivity and phototoxicity of five phenolic antioxidants with documented use in cosmetic products. A standard ROS assay was validated and applied to screen the photoreactivity of the natural phenolic antioxidants caffeic acid, ferulic acid, -coumaric acid, 3,4-dihydroxyphenylacetic acid (DOPAC), and rutin. The phototoxicity potential was determined by using a human keratinocyte cell line (HaCaT), based on the 3T3 Neutral Red Uptake phototoxicity test. Although all studied phenolic antioxidants absorbed UV/Vis radiation in the range of 290 to 700 nm, only DOPAC was able to generate singlet oxygen. The generation of reactive oxygen species is an early-stage chemical reaction as part of the phototoxicity mechanism. Yet, none of the studied compounds decreased the viability of keratinocytes after irradiation, leading to the conclusion that they do not have phototoxic potential. The data obtained with this work suggests that these compounds are safe when incorporated in cosmetic products.
Topics: Animals; Antioxidants; Biological Assay; Biological Products; Cell Line; Cell Survival; Dermatitis, Phototoxic; Humans; Mice; Molecular Structure; Polyphenols; Reactive Oxygen Species
PubMed: 35011420
DOI: 10.3390/molecules27010189 -
Dermatologic Clinics Jan 2020PUVA phototherapy is the therapeutic use of psoralens and UVA light to treat inflammatory skin diseases, with psoriasis the prototype disease. Naturally occurring... (Review)
Review
PUVA phototherapy is the therapeutic use of psoralens and UVA light to treat inflammatory skin diseases, with psoriasis the prototype disease. Naturally occurring phototoxic compounds, psoralens interact with UVA to suppress DNA synthesis and cell proliferation and induce apoptosis of inflammatory cells. Well-developed therapeutic protocols for psoriasis guide psoralen and UVA doses, treatment frequency, and safety measures, and these protocols also may be used to treat other inflammatory dermatoses.
Topics: Dermatitis; Ficusin; Humans; PUVA Therapy; Photosensitizing Agents; Psoriasis; Vitiligo
PubMed: 31753184
DOI: 10.1016/j.det.2019.08.002 -
Food and Chemical Toxicology : An... May 2018The use of this material under current conditions is supported by existing information. The material (dihydro-β-terpinyl acetate) was evaluated for genotoxicity,... (Review)
Review
The use of this material under current conditions is supported by existing information. The material (dihydro-β-terpinyl acetate) was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data from the read across analog menthyl acetate (1α,2β,5α) (CAS # 89-48-5) show that dihydro-β- terpinyl acetate is not genotoxic nor does it have skin sensitization potential. The repeated dose, reproductive and local respiratory toxicity endpoints were completed using the TTC (Threshold of Toxicological Concern) for a Cramer Class I material (0.03, 0.03 mg/kg/day and 1.4 mg/day, respectively). The phototoxicity/photoallergenicity endpoint was completed based on UV spectra. The environmental endpoints were evaluated, dihydro-β-terpinyl acetate was found not to be PBT as per the IFRA Environmental Standards and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC) are <1.
Topics: Cyclohexane Monoterpenes; Dermatitis, Phototoxic; Ecotoxicology; Humans; Lung; No-Observed-Adverse-Effect Level; Odorants; Reproduction; Risk Assessment; Safety; Skin; Teratogens; Terpenes; Toxicity Tests
PubMed: 29408617
DOI: 10.1016/j.fct.2018.01.037 -
Clinical Pharmacokinetics Aug 2017Afamelanotide, the first α-melanocyte-stimulating hormone (MSH) analogue, synthesized in 1980, was broadly investigated in all aspects of pigmentation because its... (Review)
Review
Afamelanotide, the first α-melanocyte-stimulating hormone (MSH) analogue, synthesized in 1980, was broadly investigated in all aspects of pigmentation because its activity and stability were higher than the natural hormone. Afamelanotide binds to the melanocortin-1 receptor (MC1R), and MC1R signaling increases melanin synthesis, induces antioxidant activities, enhances DNA repair processes and modulates inflammation. The loss-of-function variants of the MC1R present in fair-skinned Caucasians are less effectively activated by the natural hormone. Afamelanotide was the first α-MSH analogue to be applied to human volunteers. Ten daily doses of between 0.08 and 0.21 mg/kg in saline injected subcutaneously resulted in long-lasting skin pigmentation and enabled basic pharmacokinetics. Subcutaneous application had full bioavailability, but neither oral nor transdermal application resulted in measurable plasma concentrations or pigmentation response. Two trials in human volunteers showed that neither MC1R variants nor fair skin reduced the afamelanotide-induced increase in skin pigmentation. A controlled-release formulation optimizes administration in man and is effective at a lower dose than the daily saline injections. Promising therapeutic results were published in polymorphic light eruption, erythropoietic protoporphyria (EPP), solar urticaria, Hailey-Hailey disease and vitiligo. In 2014, afamelanotide was approved by the European Medicines Agency for the prevention of phototoxicity in adult patients with EPP. No late effects were reported in volunteers 25 years after the first exposure or after continuous long-term application of up to 8 years in EPP patients, and an immunogenic potential has been excluded. Generally, adverse effects were benign in all trials.
Topics: Administration, Cutaneous; Adult; Clinical Trials as Topic; DNA Repair; Delayed-Action Preparations; Dermatitis, Phototoxic; Dermatologic Agents; Female; Humans; Male; Pemphigus, Benign Familial; Protoporphyria, Erythropoietic; Receptor, Melanocortin, Type 1; Skin Diseases; Skin Pigmentation; Urticaria; Vitiligo; alpha-MSH
PubMed: 28063031
DOI: 10.1007/s40262-016-0501-5 -
Regulatory Toxicology and Pharmacology... Nov 2022Phototoxicity testing is required by European regulations for agrochemicals with UV/visible molar extinction/absorption coefficient (MEC) higher than 10 L x mol x cm in...
Phototoxicity testing is required by European regulations for agrochemicals with UV/visible molar extinction/absorption coefficient (MEC) higher than 10 L x mol x cm in the 290-700 nm wavelength range. Furthermore, regulations identify a need of considering human exposure in case of positive results. While in vitro OECD test guidelines are available for hazard characterisation, there is no guidance on how to utilise positive results in human exposure risk assessments. Our goal was to take a first step towards developing a NAM based tiered testing approach and a framework for non-dietary acute human dermal risk assessment for phototoxicity to agrochemicals. The proposed framework can be divided into a few steps: 1) use the OECD updated MEC values of 1000 L x mol x cm as trigger for phototoxicity testing; 2) establish a reference concentration (RfC) from in vitro phototoxicity studies using BMC approach, 3) estimate potential exposure to skin, target organ for phototoxicity, using EFSA exposure models, product specific labels and skin penetration values, and 4) phototoxicity risk assessment; 5) refinement to RfC and/or exposure estimates can be considered. Finally, case studies of a nematicide and an herbicide active substance are provided to illustrate the proposed framework.
Topics: Agrochemicals; Dermatitis, Phototoxic; Herbicides; Humans; Risk Assessment; Skin
PubMed: 36007800
DOI: 10.1016/j.yrtph.2022.105250 -
Cellular and Molecular Gastroenterology... 2019Genetic porphyrias comprise eight diseases caused by defects in the heme biosynthetic pathway that lead to accumulation of heme precursors. Consequences of porphyria... (Review)
Review
Genetic porphyrias comprise eight diseases caused by defects in the heme biosynthetic pathway that lead to accumulation of heme precursors. Consequences of porphyria include photosensitivity, liver damage and increased risk of hepatocellular carcinoma, and neurovisceral involvement, including seizures. Fluorescent porphyrins that include protoporphyrin-IX, uroporphyrin and coproporphyrin, are photo-reactive; they absorb light energy and are excited to high-energy singlet and triplet states. Decay of the porphyrin excited to ground state releases energy and generates singlet oxygen. Porphyrin-induced oxidative stress is thought to be the major mechanism of porphyrin-mediated tissue damage. Although this explains the acute photosensitivity in most porphyrias, light-induced porphyrin-mediated oxidative stress does not account for the effect of porphyrins on internal organs. Recent findings demonstrate the unique role of fluorescent porphyrins in causing subcellular compartment-selective protein aggregation. Porphyrin-mediated protein aggregation associates with nuclear deformation, cytoplasmic vacuole formation and endoplasmic reticulum dilation. Porphyrin-triggered proteotoxicity is compounded by inhibition of the proteasome due to aggregation of some of its subunits. The ensuing disruption in proteostasis also manifests in cell cycle arrest coupled with aggregation of cell proliferation-related proteins, including PCNA, cdk4 and cyclin B1. Porphyrins bind to native proteins and, in presence of light and oxygen, oxidize several amino acids, particularly methionine. Noncovalent interaction of oxidized proteins with porphyrins leads to formation of protein aggregates. In internal organs, particularly the liver, light-independent porphyrin-mediated protein aggregation occurs after secondary triggers of oxidative stress. Thus, porphyrin-induced protein aggregation provides a novel mechanism for external and internal tissue damage in porphyrias that involve fluorescent porphyrin accumulation.
Topics: Animals; Carcinoma, Hepatocellular; Dermatitis, Phototoxic; Heme; Humans; Liver; Liver Neoplasms; Mice; Oxidation-Reduction; Oxidative Stress; Photosensitivity Disorders; Porphyrias; Porphyrins; Protein Aggregates; Protoporphyrins; Uroporphyrins; Zebrafish
PubMed: 31233899
DOI: 10.1016/j.jcmgh.2019.06.006