In vitro metabolism of sunscreen compounds by liquid chromatography/high‐resolution tandem mass spectrometry

Abstract

Rationale Exposure to UV light can induce adverse effects on human health, such as photo‐aging, immunosuppression, and cancer. Sunscreens are used to prevent the absorption of UV rays, but certain UV‐filtering compounds have been shown to disrupt endocrine systems or act as carcinogens. To assess the effects of the exposure to such compounds, it is important to study the pathways by which they are biotransformed in the body. Methods Liquid chromatography coupled to high‐resolution tandem mass spectrometry (LC/HRMS/MS) was employed to evaluate the oxidative metabolism and, specifically, the formation of reactive metabolites of six active ingredients commonly used in sunscreen formulations: oxybenzone, avobenzone, homosalate, octisalate, octocrylene, and octinoxate. In vitro incubations were performed with human and rat liver microsomes in the presence of β‐nicotinamide adenine dinucleotide phosphate and glutathione. An LC/HRMS/MS method was developed to identify metabolites employing a biphenyl reversed‐phase column for separating parent molecules, metabolites, and glutathione (GSH) adducts. Results Each tested compound resulted in the formation of several metabolites, including at least one GSH adduct. Compounds containing ester groups were hydrolyzed, and some metabolites of the free acid forms were also detected. High‐resolution MS/MS data was crucial for the structural elucidation of metabolites and GSH adducts. Fragmentation pathways were proposed for all parent compounds, as well as each described metabolite and adduct. Conclusions The results of this study will help better understand the metabolism and detoxification pathways of these xenobiotics.

Practical application of the interim internal threshold of toxicological concern (iTTC): a case study based on clinical data

“…Use of the interim iTTC for the metabolites will depend on if there are existing toxicity data and/or PK data or suitable toxicological analogues for the metabolites. All of the case study chemicals, except for ecamsule, could be metabolized by the skin and/or in the systemic circulation (Guesmi et al 2020). As such, use of the interim iTTC would require consideration of the internal exposure to parent and metabolite, except for ecamsule, since it is not metabolized (according to internal unpublished data and the summary in DrugBank).…”

Comparison between endocrine activity assessed using ToxCast/Tox21 database and human plasma concentration of sunscreen active ingredients/UV filters

“…Homosalate is metabolized primarily to 3,3,5-Trimethylcyclohexanol and salicylic acid in human and rat liver microsomes ( Guesmi et al , 2020 ). The 3,3,5-trimethylcyclohexanol was not active in any of the ED assays.…”

“…The identity of plasma and urinary metabolites of the 6 UV filters were taken from literature sources based on in vitro , animal, and human studies and evaluated for activity in ToxCast/Tox21 database ( Bury et al , 2019a , b , c ; Guesmi et al , 2020 ; Hiller et al , 2019a , b ; Huang et al , 2019 ; Klotz et al , 2019 ; Okereke et al , 1993 ; Tarazona et al , 2013 ). Specifically, the metabolites identified in the references and assessed were: (1) salicylic acid and 2-ethylhexanol for octisalate, (2) salicylic acid and 3,3,5-trimethylcyclohexanol for homosalate, (3) ethyl 2-cyano-3,3-diphenylacrylate the analog of 2-cyano-3,3-diphenylacrylic acid for octocrylene, (4) 2,4-dihydroxybenzophenone (DHB), 2,2′-dihydroxy-4-methoxybenzophenone (DHMB), and 2,3,4-trihydroxbenzophenone (THB) for oxybenzone, and (5) 4-methoxycinnamic acid and 2-ethylhexanol for octinoxate.…”

Evaluation of Two Novel Hydantoin Derivatives Using Reconstructed Human Skin Model EpiskinTM: Perspectives for Application as Potential Sunscreen Agents

“…UV filters are designed for external application on the skin; however, previous studies have shown that they can be absorbed through the skin, further metabolized, and eventually bioaccumulated or excreted [ 58 ]. To more thoroughly assess the effects of the human exposure to such compounds, it is important to study the pathways by which they are biotransformed in the body [ 40 , 59 ]. HLMs represent an affordable in vitro alternative for xenobiotics such as drugs and cosmetic ingredients biotransformation studies.…”