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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Role of Xenobiotics".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 40194

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Charles University, Faculty of Pharmacy, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
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Dear Colleagues,

All living organisms are constantly in contact with xenobiotics, e.g., drugs, food dyes and additives, cosmetic preparations, and environmental contaminants. Every xenobiotic, whether intentionally or inadvertently taken, represents a potential burden and danger for the consumer. Therefore, organisms have systems through which they metabolize, deactivate, and excrete xenobiotics—the so-called drug-metabolizing enzymes. Xenobiotics and their metabolites differ in structure, physico-chemical properties, biological activity, and behaviours in organisms. The identification of emerging metabolites is essential for the formation of pharmacokinetics, toxicokinetics, and the determination of the toxicity of each xenobiotic in drug testing as well as in toxicological and environmental studies. Recently, the rapid development of analytical methods has made it possible to uncover previously undetectable metabolites.

This Special Issue of IJMS will cover a selection of recent research topics and current review articles in the field of the identification and quantification xenobiotic metabolites in various organisms (humans, animals, invertebrates, plants, etc.). Researchers are cordially invited to submit work relevant to these topics.

Prof. Dr. Barbora Szotáková
Guest Editor

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Keywords

xenobiotics
drugs
metabolites
environmental contaminants
biotransformation enzymes
drug metabolizing enzymes
drug testing
mass spectrometry
identification

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Identification of Metabolites of Xenobiotics in International Journal of Molecular Sciences (14 articles)

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Research

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16 pages, 1735 KiB

Open AccessCommunication

Biosynthesis of Rubellins in Ramularia collo-cygni—Genetic Basis and Pathway Proposition

by Francois Dussart and Dorota Jakubczyk

Int. J. Mol. Sci. 2022, 23(7), 3475; https://doi.org/10.3390/ijms23073475 - 23 Mar 2022

Cited by 3 | Viewed by 2593

Abstract

The important disease Ramularia leaf spot of barley is caused by the fungus Ramularia collo-cygni. The disease causes yield and quality losses as a result of a decrease in photosynthesis efficiency due to the appearance of necrotic spots on the leaf surface. The development of these typical Ramularia leaf spot symptoms is thought to be linked with the release of phytotoxic secondary metabolites called rubellins in the host. However, to date, neither the biosynthetic pathways leading to the production of these metabolites nor their exact role in disease development are known. Using a combined in silico genetic and biochemistry approach, we interrogated the genome of R. collo-cygni to identify a putative rubellin biosynthetic gene cluster. Here we report the identification of a gene cluster containing homologues of genes involved in the biosynthesis of related anthraquinone metabolites in closely related fungi. A putative pathway to rubellin biosynthesis involving the genes located on the candidate cluster is also proposed. Full article

(This article belongs to the Special Issue Identification of Metabolites of Xenobiotics 2.0)

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16 pages, 1792 KiB

Open AccessArticle

New Glycosylated Dihydrochalcones Obtained by Biotransformation of 2′-Hydroxy-2-methylchalcone in Cultures of Entomopathogenic Filamentous Fungi

by Agnieszka Krawczyk-Łebek, Monika Dymarska, Tomasz Janeczko and Edyta Kostrzewa-Susłow

Int. J. Mol. Sci. 2021, 22(17), 9619; https://doi.org/10.3390/ijms22179619 - 5 Sep 2021

Cited by 14 | Viewed by 2482

Abstract

Flavonoids, including chalcones, are more stable and bioavailable in the form of glycosylated and methylated derivatives. The combined chemical and biotechnological methods can be applied to obtain such compounds. In the present study, 2′-hydroxy-2-methylchalcone was synthesized and biotransformed in the cultures of entomopathogenic filamentous fungi Beauveria bassiana KCH J1.5, Isaria fumosorosea KCH J2 and Isaria farinosa KCH J2.6, which have been known for their extensive enzymatic system and ability to perform glycosylation of flavonoids. As a result, five new glycosylated dihydrochalcones were obtained. Biotransformation of 2′-hydroxy-2-methylchalcone by B. bassiana KCH J1.5 resulted in four glycosylated dihydrochalcones: 2′-hydroxy-2-methyldihydrochalcone 3′-O-β-d-(4″-O-methyl)-glucopyranoside, 2′,3-dihydroxy-2-methyldihydrochalcone 3′-O-β-d-(4″-O-methyl)-glucopyranoside, 2′-hydroxy-2-hydroxymethyldihydrochalcone 3′-O-β-d-(4″-O-methyl)-glucopyranoside, and 2′,4-dihydroxy-2-methyldihydrochalcone 3′-O-β-d-(4″-O-methyl)-glucopyranoside. In the culture of I. fumosorosea KCH J2 only one product was formed—3-hydroxy-2-methyldihydrochalcone 2′-O-β-d-(4″-O-methyl)-glucopyranoside. Biotransformation performed by I. farinosa KCH J2.6 resulted in the formation of two products: 2′-hydroxy-2-methyldihydrochalcone 3′-O-β-d-(4″-O-methyl)-glucopyranoside and 2′,3-dihydroxy-2-methyldihydrochalcone 3′-O-β-d-(4″-O-methyl)-glucopyranoside. The structures of all obtained products were established based on the NMR spectroscopy. All products mentioned above may be used in further studies as potentially bioactive compounds with improved stability and bioavailability. These compounds can be considered as flavor enhancers and potential sweeteners. Full article

(This article belongs to the Special Issue Identification of Metabolites of Xenobiotics 2.0)

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20 pages, 4493 KiB

Open AccessArticle

Fungal Biotransformation of 2′-Methylflavanone and 2′-Methylflavone as a Method to Obtain Glycosylated Derivatives

by Agnieszka Krawczyk-Łebek, Monika Dymarska, Tomasz Janeczko and Edyta Kostrzewa-Susłow

Int. J. Mol. Sci. 2021, 22(17), 9617; https://doi.org/10.3390/ijms22179617 - 5 Sep 2021

Cited by 8 | Viewed by 2507

Abstract

Methylated flavonoids are promising pharmaceutical agents due to their improved metabolic stability and increased activity compared to unmethylated forms. The biotransformation in cultures of entomopathogenic filamentous fungi is a valuable method to obtain glycosylated flavones and flavanones with increased aqueous solubility and bioavailability. In the present study, we combined chemical synthesis and biotransformation to obtain methylated and glycosylated flavonoid derivatives. In the first step, we synthesized 2′-methylflavanone and 2′-methylflavone. Afterwards, both compounds were biotransformed in the cultures of two strains of entomopathogenic filamentous fungi Beauveria bassiana KCH J1.5 and Isaria fumosorosea KCH J2. We determined the structures of biotransformation products based on NMR spectroscopy. Biotransformations of 2′-methyflavanone in the culture of B. bassiana KCH J1.5 resulted in three glycosylated flavanones: 2′-methylflavanone 6-O-β-d-(4″-O-methyl)-glucopyranoside, 3′-hydroxy-2′-methylflavanone 6-O-β-d-(4″-O-methyl)-glucopyranoside, and 2-(2′-methylphenyl)-chromane 4-O-β-d-(4″-O-methyl)-glucopyranoside, whereas in the culture of I. fumosorosea KCH J2, two other products were obtained: 2′-methylflavanone 3′-O-β-d-(4″-O-methyl)-glucopyranoside and 2-methylbenzoic acid 4-O-β-d-(4′-O-methyl)-glucopyranoside. 2′-Methylflavone was effectively biotransformed only by I. fumosorosea KCH J2 into three derivatives: 2′-methylflavone 3′-O-β-d-(4″-O-methyl)-glucopyranoside, 2′-methylflavone 4′-O-β-d-(4″-O-methyl)-glucopyranoside, and 2′-methylflavone 5′-O-β-d-(4″-O-methyl)-glucopyranoside. All obtained glycosylated flavonoids have not been described in the literature until now and need further research on their biological activity and pharmacological efficacy as potential drugs. Full article

(This article belongs to the Special Issue Identification of Metabolites of Xenobiotics 2.0)

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22 pages, 6241 KiB

Open AccessArticle

Investigation of Bemethyl Biotransformation Pathways by Combination of LC–MS/HRMS and In Silico Methods

by Daria A. Belinskaia, Elena I. Savelieva, Georgy V. Karakashev, Olga I. Orlova, Mikhail A. Leninskii, Nataliia S. Khlebnikova, Natalia N. Shestakova and Alexandra R. Kiskina

Int. J. Mol. Sci. 2021, 22(16), 9021; https://doi.org/10.3390/ijms22169021 - 21 Aug 2021

Cited by 3 | Viewed by 3261

Abstract

Bemethyl is an actoprotector, an antihypoxant, and a moderate psychostimulant. Even though the therapeutic effectiveness of bemethyl is well documented, there is a gap in knowledge regarding its metabolic products and their quantitative and qualitative characteristics. Since 2018, bemethyl is included to the Monitoring Program of the World Anti-Doping Agency, which highlights the challenge of identifying its urinary metabolites. The objective of the study was to investigate the biotransformation pathways of bemethyl using a combination of liquid chromatography-high-resolution mass spectrometry and in silico studies. Metabolites were analyzed in a 24 h rat urine collected after oral administration of bemethyl at a single dose of 330 mg/kg. The urine samples were prepared for analysis by a procedure developed in the present work and analyzed by high performance liquid chromatography–tandem mass spectrometry. For the first time, nine metabolites of bemethyl with six molecular formulas were identified in rat urine. The most abundant metabolite was a benzimidazole–acetylcysteine conjugate; this biotransformation pathway is associated with the detoxification of xenobiotics. The BioTransformer and GLORY computational tools were used to predict bemethyl metabolites in silico. The molecular docking of bemethyl and its derivatives to the binding site of glutathione S-transferase has revealed the mechanism of bemethyl conjugation with glutathione. The findings will help to understand the pharmacokinetics and pharmacodynamics of actoprotectors and to improve antihypoxant and adaptogenic therapy. Full article

(This article belongs to the Special Issue Identification of Metabolites of Xenobiotics 2.0)

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20 pages, 3616 KiB

Open AccessArticle

Simple and Rapid Method for Wogonin Preparation and Its Biotransformation

by Tomasz Tronina, Monika Mrozowska, Agnieszka Bartmańska, Jarosław Popłoński, Sandra Sordon and Ewa Huszcza

Int. J. Mol. Sci. 2021, 22(16), 8973; https://doi.org/10.3390/ijms22168973 - 20 Aug 2021

Cited by 4 | Viewed by 2880

Abstract

Wogonin is one of the most active flavonoids from Scutellaria baicalensis Georgi (baikal skullcap), widely used in traditional Chinese medicine. It exhibits a broad spectrum of health-promoting and therapeutic activities. Together with baicalein, it is considered to be the one of main active ingredients of Chinese medicines for the management of COVID-19. However, therapeutic use of wogonin may be limited due to low market availability connected with its low content in baikal skullcap and lack of efficient preparative methods for obtaining this compound. Although the amount of wogonin in skullcap root often does not exceed 0.5%, this material is rich in wogonin glucuronide, which may be used as a substrate for wogonin production. In the present study, a rapid, simple, cheap and effective method of wogonin and baicalein preparation, which provides gram quantities of both flavonoids, is proposed. The obtained wogonin was used as a substrate for biotransformation. Thirty-six microorganisms were tested in screening studies. The most efficient were used in enlarged scale transformations to determine metabolism of this xenobiotic. The major phase I metabolism product was 4′-hydroxywogonin—a rare flavonoid which exhibits anticancer activity—whereas phase II metabolism products were glucosides of wogonin. The present studies complement and extend the knowledge on the effect of substitution of A- and B-ring on the regioselective glycosylation of flavonoids catalyzed by microorganisms. Full article

(This article belongs to the Special Issue Identification of Metabolites of Xenobiotics 2.0)

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19 pages, 5353 KiB

Open AccessArticle

In Vitro Evaluation of Rigosertib Antitumoral and Radiosensitizing Effects against Human Cholangiocarcinoma Cells

by Alessio Malacrida, Roberta Rigolio, Luigi Celio, Silvia Damian, Guido Cavaletti, Vincenzo Mazzaferro and Mariarosaria Miloso

Int. J. Mol. Sci. 2021, 22(15), 8230; https://doi.org/10.3390/ijms22158230 - 30 Jul 2021

Cited by 4 | Viewed by 2390

Abstract

Cholangiocarcinoma is the first most common cancer of the biliary tract. To date, surgical resection is the only potentially curative option, but it is possible only for a limited percentage of patients, and in any case survival rate is quite low. Moreover, cholangiocarcinoma is often chemotherapy-resistant, and the only drug with a significant benefit for patient’s survival is Gemcitabine. It is necessary to find new drugs or combination therapies to treat nonresectable cholangiocarcinoma and improve the overall survival rate of patients. In this work, we evaluate in vitro the antitumoral effects of Rigosertib, a multi-kinase inhibitor in clinical development, against cholangiocarcinoma EGI-1 cell lines. Rigosertib impairs EGI-1 cell viability in a dose- and time-dependent manner, reversibility is dose-dependent, and significant morphological and nuclear alterations occur. Moreover, Rigosertib induces the arrest of the cell cycle in the G2/M phase, increases autophagy, and inhibits proteasome, cell migration, and invasion. Lastly, Rigosertib shows to be a stronger radiosensitizer than Gemcitabine and 5-Fluorouracil. In conclusion, Rigosertib could be a potential therapeutic option, alone or in combination with radiations, for nonresectable patients with cholangiocarcinoma. Full article

(This article belongs to the Special Issue Identification of Metabolites of Xenobiotics 2.0)

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16 pages, 1866 KiB

Open AccessArticle

Microbial Synthesis and Evaluation of Fungistatic Activity of 3-Butyl-3-hydroxyphthalide, the Mammalian Metabolite of 3-n-Butylidenephthalide

by Joanna Gach, Teresa Olejniczak, Piotr Krężel and Filip Boratyński

Int. J. Mol. Sci. 2021, 22(14), 7600; https://doi.org/10.3390/ijms22147600 - 15 Jul 2021

Cited by 8 | Viewed by 2483

Abstract

Phthalides are bioactive compounds that naturally occur in the family Apiaceae. Considering their potentially versatile applications, it is desirable to determine their physical properties, activity and metabolic pathways. This study aimed to examine the utility of whole-cell biocatalysts for obtaining 3-butyl-3-hydroxyphthalide, which is the metabolite formulated during mammalian metabolism of 3-n-butylidenephthalide. We performed transformations using 10 strains of fungi, five of which efficiently produced 3-butyl-3-hydroxyphthalide. The product yield, determined by high-performance liquid chromatography, reached 97.6% when Aspergillus candidus AM 386 was used as the biocatalyst. Increasing the scale of the process resulted in isolation yields of 29–45% after purification via reversed-phase thin layer chromatography, depending on the strain of the microorganism used. We proposed different mechanisms for product formation; however, hydration of 3-n-butylidenephthalide seems to be the most probable. Additionally, all phthalides were tested against clinical strains of Candida albicans using the microdilution method. Two phthalides showed a minimum inhibitory concentration, required to inhibit the growth of 50% of organisms, below 50 µg/mL. The 3-n-butylidenephthalide metabolite was generally inactive, and this feature in combination with its low lipophilicity suggests its involvement in the detoxification pathway. The log P value of tested compounds was in the range of 2.09–3.38. Full article

(This article belongs to the Special Issue Identification of Metabolites of Xenobiotics 2.0)

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11 pages, 1936 KiB

Open AccessArticle

Soybean (Glycine max) Is Able to Absorb, Metabolize and Accumulate Fenbendazole in All Organs Including Beans

by Radka Podlipná, Martina Navrátilová, Lucie Raisová Stuchlíková, Kateřina Moťková, Lenka Langhansová, Lenka Skálová and Barbora Szotáková

Int. J. Mol. Sci. 2021, 22(13), 6647; https://doi.org/10.3390/ijms22136647 - 22 Jun 2021

Cited by 2 | Viewed by 2088

Abstract

Although manure is an important source of minerals and organic compounds it represents a certain risk of spreading the veterinary drugs in the farmland and their permeation to human food. We tested the uptake of the anthelmintic drug fenbendazole (FBZ) by soybean, a common crop plant, from the soil and its biotransformation and accumulation in different soybean organs, including beans. Soybeans were cultivated in vitro or grown in a greenhouse in pots. FBZ was extensively metabolized in roots of in vitro seedlings, where sixteen metabolites were identified, and less in leaves, where only two metabolites were found. The soybeans in greenhouse absorbed FBZ by roots and translocated it to the leaves, pods, and beans. In roots, leaves, and pods two metabolites were identified. In beans, FBZ and one metabolite was found. FBZ exposure did not affect the plant fitness or yield, but reduced activities of some antioxidant enzymes and isoflavonoids content in the beans. In conclusion, manure or biosolids containing FBZ and its metabolites represent a significant risk of these pharmaceuticals entering food consumed by humans or animal feed. In addition, the presence of these drugs in plants can affect plant metabolism, including the production of isoflavonoids. Full article

(This article belongs to the Special Issue Identification of Metabolites of Xenobiotics 2.0)

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Review

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22 pages, 2042 KiB

Open AccessReview

Current View on the Mechanisms of Alcohol-Mediated Toxicity

by Anna Birková, Beáta Hubková, Beáta Čižmárová and Beáta Bolerázska

Int. J. Mol. Sci. 2021, 22(18), 9686; https://doi.org/10.3390/ijms22189686 - 7 Sep 2021

Cited by 29 | Viewed by 5239

Abstract

Alcohol is a psychoactive substance that is widely used and, unfortunately, often abused. In addition to acute effects such as intoxication, it may cause many chronic pathological conditions. Some of the effects are very well described and explained, but there are still gaps in the explanation of empirically co-founded dysfunction in many alcohol-related conditions. This work focuses on reviewing actual knowledge about the toxic effects of ethanol and its degradation products. Full article

(This article belongs to the Special Issue Identification of Metabolites of Xenobiotics 2.0)

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15 pages, 576 KiB

Open AccessReview

Metabolomic Biomarkers in Gestational Diabetes Mellitus: A Review of the Evidence

by Simon Alesi, Drishti Ghelani, Kate Rassie and Aya Mousa

Int. J. Mol. Sci. 2021, 22(11), 5512; https://doi.org/10.3390/ijms22115512 - 24 May 2021

Cited by 54 | Viewed by 7697

Abstract

Gestational diabetes mellitus (GDM) is the fastest growing type of diabetes, affecting between 2 to 38% of pregnancies worldwide, varying considerably depending on diagnostic criteria used and sample population studied. Adverse obstetric outcomes include an increased risk of macrosomia, and higher rates of stillbirth, instrumental delivery, and birth trauma. Metabolomics, which is a platform used to analyse and characterise a large number of metabolites, is increasingly used to explore the pathophysiology of cardiometabolic conditions such as GDM. This review aims to summarise metabolomics studies in GDM (from inception to January 2021) in order to highlight prospective biomarkers for diagnosis, and to better understand the dysfunctional metabolic pathways underlying the condition. We found that the most commonly deranged pathways in GDM include amino acids (glutathione, alanine, valine, and serine), carbohydrates (2-hydroxybutyrate and 1,5-anhydroglucitol), and lipids (phosphatidylcholines and lysophosphatidylcholines). We also highlight the possibility of using certain metabolites as predictive markers for developing GDM, with the use of highly stratified modelling techniques. Limitations for metabolomic research are evaluated, and future directions for the field are suggested to aid in the integration of these findings into clinical practice. Full article

(This article belongs to the Special Issue Identification of Metabolites of Xenobiotics 2.0)

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27 pages, 991 KiB

Open AccessReview

In Vitro and Vivo Identification, Metabolism and Action of Xenoestrogens: An Overview

by Li-Hsuan Wang, Li-Ru Chen and Kuo-Hu Chen

Int. J. Mol. Sci. 2021, 22(8), 4013; https://doi.org/10.3390/ijms22084013 - 13 Apr 2021

Cited by 19 | Viewed by 5262

Abstract

Xenoestrogens (XEs) are substances that imitate endogenous estrogens to affect the physiologic functions of humans or other animals. As endocrine disruptors, they can be either synthetic or natural chemical compounds derived from diet, pesticides, cosmetics, plastics, plants, industrial byproducts, metals, and medications. By mimicking the chemical structure that is naturally occurring estrogen compounds, synthetic XEs, such as polychlorinated biphenyls (PCBs), bisphenol A (BPA), and diethylstilbestrol (DES), are considered the focus of a group of exogenous chemical. On the other hand, nature phytoestrogens in soybeans can also serve as XEs to exert estrogenic activities. In contrast, some XEs are not similar to estrogens in structure and can affect the physiologic functions in ways other than ER-ERE ligand routes. Studies have confirmed that even the weakly active compounds could interfere with the hormonal balance with persistency or high concentrations of XEs, thus possibly being associated with the occurrence of the reproductive tract or neuroendocrine disorders and congenital malformations. However, XEs are most likely to exert tissue-specific and non-genomic actions when estrogen concentrations are relatively low. Current research has reported that there is not only one factor affected by XEs, but opposite directions are also found on several occasions, or even different components stem from the identical endocrine pathway; thus, it is more challenging and unpredictable of the physical health. This review provides a summary of the identification, detection, metabolism, and action of XEs. However, many details of the underlying mechanisms remain unknown and warrant further investigation. Full article

(This article belongs to the Special Issue Identification of Metabolites of Xenobiotics 2.0)

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