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

Deadline for manuscript submissions: closed (31 October 2013) | Viewed by 100887

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Dr. Michael Iba

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Guest Editor

Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA
Interests: developmental toxicology; xenobiotic metabolism/activation; aromatic amine toxicity; volatile organic compound toxicity; health effects of tobacco smoke

Special Issue Information

Dear Colleagues,

Drug metabolism is a process by which drug molecules undergo enzyme-catalyzed chemical transformations into products that are more hydrophilic and more easily excreted in urine or bile. The process can also yield products that are more pharmacologically active or more toxic than their precursors. Enzymes involved in drug metabolism typically catalyze the oxidation, reduction and hydrolysis of drug molecules (phase I reactions), and conjugation of the drugs or their metabolites with endogenous compounds (phase II reactions). The same enzymes also catalyze the metabolism of a wide variety of other xenobiotics as well as some endogenous compounds.

While the liver is quantitatively the major organ of drug metabolism, extrahepatic tissues can also metabolize drugs but at rates usually lower than the liver. Nevertheless, extrahepatic metabolism may play a significant role in the efficacy and/or characteristic organ-selective toxicity of certain drugs.

The endoplasmic reticulum (ER) is a major subcellular localization of drug metabolizing enzymes, particularly the drug-metabolizing cytochrome P450 (CYP) enzymes, which catalyze the majority of all phase I drug metabolism reactions. Recent studies have localized CYP enzymes to other subcellular fractions, including mitochondria. The mechanisms by which the enzymes are targeted to specific subcellular organelles and the physiological, pharmacological and toxicological significance of non-ER CYP enzymes is an active area of research.

Hepatic metabolism of certain drugs requires transporter-mediated uptake of the drugs by hepatocytes. Deficiency in the transporters has been associated with impaired metabolism of the drugs, with consequent enhancement of their adverse effects. Thus, transport may play a significant role in drug metabolism. Other factors known to significantly influence drug metabolism include age, sex, physiological/disease status, and genetics. Knowledge of the mechanisms by which these factors influence drug metabolism is necessary for the effective and safe use of therapeutic dugs and for the development of effective measures against environmental toxicants.

This special issue is intended to serve as a platform for updating information on drug metabolism and for presenting advances in basic and clinical research in the field.

Prof. Dr. Michael Iba
Guest Editor

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Keywords

age, sexual and genetic variability
bioactivation
cytochrome P450 and non-P450 enzymes
detoxification
extrahepatic
subcellular fractions
phase I and phase II metabolism
transport

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Published Papers (13 papers)

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Research

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783 KiB

Open AccessArticle

Detoxification of Toxic Phorbol Esters from Malaysian Jatropha curcas Linn. Kernel by Trichoderma spp. and Endophytic Fungi

by Azhar Najjar, Norhani Abdullah, Wan Zuhainis Saad, Syahida Ahmad, Ehsan Oskoueian, Faridah Abas and Youssuf Gherbawy

Int. J. Mol. Sci. 2014, 15(2), 2274-2288; https://doi.org/10.3390/ijms15022274 - 5 Feb 2014

Cited by 25 | Viewed by 7737

Abstract

The presence of phorbol esters (PEs) with toxic properties limits the use of Jatropha curcas kernel in the animal feed industry. Therefore, suitable methods to detoxify PEs have to be developed to render the material safe as a feed ingredient. In the present study, the biological treatment of the extracted PEs-rich fraction with non-pathogenic fungi (Trichoderma harzianum JQ350879.1, T. harzianum JQ517493.1, Paecilomyces sinensis JQ350881.1, Cladosporium cladosporioides JQ517491.1, Fusarium chlamydosporum JQ350882.1, F. chlamydosporum JQ517492.1 and F. chlamydosporum JQ350880.1) was conducted by fermentation in broth cultures. The PEs were detected by liquid chromatography-diode array detector-electrospray ionization mass spectrometry (LC-DAD-ESIMS) and quantitatively monitored by HPLC using phorbol-12-myristate 13-acetate as the standard. At day 30 of incubation, two T. harzianum spp., P. sinensis and C. cladosporioides significantly (p < 0.05) removed PEs with percentage losses of 96.9%–99.7%, while F. chlamydosporum strains showed percentage losses of 88.9%–92.2%. All fungal strains could utilize the PEs-rich fraction for growth. In the cytotoxicity assay, cell viabilities of Chang liver and NIH 3T3 fibroblast cell lines were less than 1% with the untreated PEs-rich fraction, but 84.3%–96.5% with the fungal treated PEs-rich fraction. There was no inhibition on cell viability for normal fungal growth supernatants. To conclude, Trichoderma spp., Paecilomyces sp. and Cladosporium sp. are potential microbes for the detoxification of PEs. Full article

(This article belongs to the Special Issue Xenobiotic Metabolism)

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6746 KiB

Open AccessArticle

Towards Automated Binding Affinity Prediction Using an Iterative Linear Interaction Energy Approach

by C. Ruben Vosmeer, René Pool, Mariël F. Van Stee, Lovorka Perić-Hassler, Nico P. E. Vermeulen and Daan P. Geerke

Int. J. Mol. Sci. 2014, 15(1), 798-816; https://doi.org/10.3390/ijms15010798 - 9 Jan 2014

Cited by 20 | Viewed by 6492

Abstract

Binding affinity prediction of potential drugs to target and off-target proteins is an essential asset in drug development. These predictions require the calculation of binding free energies. In such calculations, it is a major challenge to properly account for both the dynamic nature of the protein and the possible variety of ligand-binding orientations, while keeping computational costs tractable. Recently, an iterative Linear Interaction Energy (LIE) approach was introduced, in which results from multiple simulations of a protein-ligand complex are combined into a single binding free energy using a Boltzmann weighting-based scheme. This method was shown to reach experimental accuracy for flexible proteins while retaining the computational efficiency of the general LIE approach. Here, we show that the iterative LIE approach can be used to predict binding affinities in an automated way. A workflow was designed using preselected protein conformations, automated ligand docking and clustering, and a (semi-)automated molecular dynamics simulation setup. We show that using this workflow, binding affinities of aryloxypropanolamines to the malleable Cytochrome P450 2D6 enzyme can be predicted without a priori knowledge of dominant protein-ligand conformations. In addition, we provide an outlook for an approach to assess the quality of the LIE predictions, based on simulation outcomes only. Full article

(This article belongs to the Special Issue Xenobiotic Metabolism)

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606 KiB

Open AccessArticle

Chimeric Mice with Humanized Livers: A Unique Tool for in Vivo and in Vitro Enzyme Induction Studies

by Masakazu Kakuni, Chihiro Yamasaki, Asato Tachibana, Yasumi Yoshizane, Yuji Ishida and Chise Tateno

Int. J. Mol. Sci. 2014, 15(1), 58-74; https://doi.org/10.3390/ijms15010058 - 20 Dec 2013

Cited by 40 | Viewed by 7326

Abstract

We performed in vivo and in vitro studies to determine the induction of human cytochrome P450 (CYP) using chimeric mice with humanized liver (PXB-mice^®) and human hepatocytes isolated from the PXB-mice (PXB-cells), which were derived from the same donor. For the in vivo study, PXB-mice were injected with 3-methylcholanthrene (3-MC, 2 or 20 mg/kg) or rifampicin (0.1 or 10 mg/kg) for four days. For the in vitro study, PXB-cells were incubated with 3-MC (10, 50, or 250 ng/mL) or with rifampicin (5 or 25 μg/mL). The CYP1A1 and 1A2, and CYP3A4 mRNA expression levels increased significantly in the PXB-mouse livers with 20 mg/kg of 3-MC (C_max, 12.2 ng/mL), and 10 mg/kg rifampicin (C_max, 6.9 µg/mL), respectively. The CYP1A1 mRNA expression level increased significantly in PXB-cells with 250 ng/mL of 3-MC, indicating lower sensitivity than in vivo. The CYP1A2 and CYP3A4 mRNA expression levels increased significantly with 50 ng/mL of 3-MC, and 5 μg/mL of rifampicin, respectively, which indicated that the sensitivities were similar between in vivo and in vitro studies. In conclusion, PXB-mice and PXB-cells provide a robust model as an intermediate between in vivo and in vitro human metabolic enzyme induction studies. Full article

(This article belongs to the Special Issue Xenobiotic Metabolism)

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1176 KiB

Open AccessArticle

CYP 2D6 Binding Affinity Predictions Using Multiple Ligand and Protein Conformations

by Lovorka Perić-Hassler, Eva Stjernschantz, Chris Oostenbrink and Daan P. Geerke

Int. J. Mol. Sci. 2013, 14(12), 24514-24530; https://doi.org/10.3390/ijms141224514 - 17 Dec 2013

Cited by 29 | Viewed by 7209

Abstract

Because of the large flexibility and malleability of Cytochrome P450 enzymes (CYPs), in silico prediction of CYP binding affinities to drugs and other xenobiotic compounds is a true challenge. In the current work, we use an iterative linear interaction energy (LIE) approach to compute CYP binding affinities from molecular dynamics (MD) simulation. In order to improve sampling of conformational space, we combine results from simulations starting with different relevant protein-ligand geometries. For calculated binding free energies of a set of thiourea compounds binding to the flexible CYP 2D6 isoform, improved correlation with experiment was obtained by combining results of MD runs starting from distinct protein conformations and ligand-binding orientations. This accuracy was obtained from relatively short MD simulations, which makes our approach computationally attractive for automated calculations of ligand-binding affinities to flexible proteins such as CYPs. Full article

(This article belongs to the Special Issue Xenobiotic Metabolism)

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664 KiB

Open AccessArticle

Effects of Ospemifene on Drug Metabolism Mediated by Cytochrome P450 Enzymes in Humans in Vitro and in Vivo

by Miia Turpeinen, Jouko Uusitalo, Terhi Lehtinen, Marita Kailajärvi, Olavi Pelkonen, Jouni Vuorinen, Pasi Tapanainen, Camilla Stjernschantz, Risto Lammintausta and Mika Scheinin

Int. J. Mol. Sci. 2013, 14(7), 14064-14075; https://doi.org/10.3390/ijms140714064 - 5 Jul 2013

Cited by 11 | Viewed by 7466

Abstract

The objective of these investigations was to determine the possible effects of the novel selective estrogen receptor modulator, ospemifene, on cytochrome P450 (CYP)-mediated drug metabolism. Ospemifene underwent testing for possible effects on CYP enzyme activity in human liver microsomes and in isolated human hepatocytes. Based on the results obtained in vitro, three Phase 1 crossover pharmacokinetic studies were conducted in healthy postmenopausal women to assess the in vivo effects of ospemifene on CYP-mediated drug metabolism. Ospemifene and its main metabolites 4-hydroxyospemifene and 4'-hydroxyospemifene weakly inhibited a number of CYPs (CYP2B6, CYP2C9, CYP2C19, CYP2C8, and CYP2D6) in vitro. However, only CYP2C9 activity was inhibited by 4-hydroxyospemifene at clinically relevant concentrations. Induction of CYPs by ospemifene in cultured human hepatocytes was 2.4-fold or less. The in vivo studies showed that ospemifene did not have significant effects on the areas under the plasma concentration-time curves of the tested CYP substrates warfarin (CYP2C9), bupropion (CYP2B6) and omeprazole (CYP2C19), demonstrating that pretreatment with ospemifene did not alter their metabolism. Therefore, the risk that ospemifene will affect the pharmacokinetics of drugs that are substrates for CYP enzymes is low. Full article

(This article belongs to the Special Issue Xenobiotic Metabolism)

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1130 KiB

Open AccessArticle

Chicken Cytochrome P450 1A5 Is the Key Enzyme for Metabolizing T-2 Toxin to 3'OH-T-2

by Shufeng Shang, Jun Jiang and Yiqun Deng

Int. J. Mol. Sci. 2013, 14(6), 10809-10818; https://doi.org/10.3390/ijms140610809 - 23 May 2013

Cited by 26 | Viewed by 7300

Abstract

The transmission of T-2 toxin and its metabolites into the edible tissues of poultry has potential effects on human health. We report that T-2 toxin significantly induces CYP1A4 and CYP1A5 expression in chicken embryonic hepatocyte cells. The enzyme activity assays of CYP1A4 and CYP1A5 heterologously expressed in HeLa cells indicate that only CYP1A5 metabolizes T-2 to 3'OH-T-2 by the 3'-hydroxylation of isovaleryl groups. In vitro enzyme assays of recombinant CYP1A5 expressed in DH5α further confirm that CYP1A5 can convert T-2 into TC-1 (3'OH-T-2). Therefore, CYP1A5 is critical for the metabolism of trichothecene mycotoxin in chickens. Full article

(This article belongs to the Special Issue Xenobiotic Metabolism)

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Review

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196 KiB

Open AccessReview

Drug-Induced Hepatotoxicity: Metabolic, Genetic and Immunological Basis

by Dolores B. Njoku

Int. J. Mol. Sci. 2014, 15(4), 6990-7003; https://doi.org/10.3390/ijms15046990 - 22 Apr 2014

Cited by 60 | Viewed by 10419

Abstract

Drug-induced hepatotoxicity is a significant cause of acute liver failure and is usually the primary reason that therapeutic drugs are removed from the commercial market. Multiple mechanisms can culminate in drug hepatotoxicity. Metabolism, genetics and immunology separately and in concert play distinct and overlapping roles in this process. This review will cover papers we feel have addressed these mechanisms of drug-induced hepatotoxicity in adults following the consumption of commonly used medications. The aim is to generate discussion around “trigger point” papers where the investigators generated new science or provided additional contribution to existing science. Hopefully these discussions will assist in uncovering key areas that need further attention. Full article

(This article belongs to the Special Issue Xenobiotic Metabolism)

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202 KiB

Open AccessReview

Xenobiotic Metabolism: The Effect of Acute Kidney Injury on Non-Renal Drug Clearance and Hepatic Drug Metabolism

by John Dixon, Katie Lane, Iain MacPhee and Barbara Philips

Int. J. Mol. Sci. 2014, 15(2), 2538-2553; https://doi.org/10.3390/ijms15022538 - 13 Feb 2014

Cited by 44 | Viewed by 8059

Abstract

Acute kidney injury (AKI) is a common complication of critical illness, and evidence is emerging that suggests AKI disrupts the function of other organs. It is a recognized phenomenon that patients with chronic kidney disease (CKD) have reduced hepatic metabolism of drugs, via the cytochrome P450 (CYP) enzyme group, and drug dosing guidelines in AKI are often extrapolated from data obtained from patients with CKD. This approach, however, is flawed because several confounding factors exist in AKI. The data from animal studies investigating the effects of AKI on CYP activity are conflicting, although the results of the majority do suggest that AKI impairs hepatic CYP activity. More recently, human study data have also demonstrated decreased CYP activity associated with AKI, in particular the CYP3A subtypes. Furthermore, preliminary data suggest that patients expressing the functional allele variant CYP3A5*1 may be protected from the deleterious effects of AKI when compared with patients homozygous for the variant CYP3A5*3, which codes for a non-functional protein. In conclusion, there is a need to individualize drug prescribing, particularly for the more sick and vulnerable patients, but this needs to be explored in greater depth. Full article

(This article belongs to the Special Issue Xenobiotic Metabolism)

507 KiB

Open AccessReview

Establishment of Metabolism and Transport Pathways in the Rodent and Human Fetal Liver

by Jamie E. Moscovitz and Lauren M. Aleksunes

Int. J. Mol. Sci. 2013, 14(12), 23801-23827; https://doi.org/10.3390/ijms141223801 - 6 Dec 2013

Cited by 27 | Viewed by 8822

Abstract

The ultimate fate of drugs and chemicals in the body is largely regulated by hepatic uptake, metabolism, and excretion. The liver acquires the functional ability to metabolize and transport chemicals during the perinatal period of development. Research using livers from fetal and juvenile rodents and humans has begun to reveal the timing, key enzymes and transporters, and regulatory factors that are responsible for the establishment of hepatic phase I and II metabolism as well as transport. The majority of this research has been limited to relative mRNA and protein quantification. However, the recent utilization of novel technology, such as RNA-Sequencing, and the improved availability and refinement of functional activity assays, has begun to provide more definitive information regarding the extent of hepatic drug disposition in the developing fetus. The goals of this review are to provide an overview of the early regulation of the major phase I and II enzymes and transporters in rodent and human livers and to highlight potential mechanisms that control the ontogeny of chemical metabolism and excretion pathways. Full article

(This article belongs to the Special Issue Xenobiotic Metabolism)

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396 KiB

Open AccessReview

Modeling Human Liver Biology Using Stem Cell-Derived Hepatocytes

by Pingnan Sun, Xiaoling Zhou, Sarah L. Farnworth, Arvind H. Patel and David C. Hay

Int. J. Mol. Sci. 2013, 14(11), 22011-22021; https://doi.org/10.3390/ijms141122011 - 6 Nov 2013

Cited by 8 | Viewed by 7451

Abstract

Stem cell-derived hepatocytes represent promising models to study human liver biology and disease. This concise review discusses the recent progresses in the field, with a focus on human liver disease, drug metabolism and virus infection. Full article

(This article belongs to the Special Issue Xenobiotic Metabolism)

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247 KiB

Open AccessReview

Regulation of 3β-Hydroxysteroid Dehydrogenase/Δ⁵-Δ⁴ Isomerase: A Review

by Martin Krøyer Rasmussen, Bo Ekstrand and Galia Zamaratskaia

Int. J. Mol. Sci. 2013, 14(9), 17926-17942; https://doi.org/10.3390/ijms140917926 - 2 Sep 2013

Cited by 70 | Viewed by 8438

Abstract

This review focuses on the expression and regulation of 3β-hydroxysteroid dehydrogenase/Δ⁵-Δ⁴ isomerase (3β-HSD), with emphasis on the porcine version. 3β-HSD is often associated with steroidogenesis, but its function in the metabolism of both steroids and xenobiotics is more obscure. Based on currently available literature covering humans, rodents and pigs, this review provides an overview of the present knowledge concerning the regulatory mechanisms for 3β-HSD at all omic levels. The HSD isoenzymes are essential in steroid hormone metabolism, both in the synthesis and degradation of steroids. They display tissue-specific expression and factors influencing their activity, which therefore indicates their tissue-specific responses. 3β-HSD is involved in the synthesis of a number of natural steroid hormones, including progesterone and testosterone, and the hepatic degradation of the pheromone androstenone. In general, a number of signaling and regulatory pathways have been demonstrated to influence 3β-HSD transcription and activity, e.g., JAK-STAT, LH/hCG, ERα, AR, SF-1 and PPARα. The expression and enzymic activity of 3β-HSD are also influenced by external factors, such as dietary composition. Much of the research conducted on porcine 3β-HSD is motivated by its importance for the occurrence of the boar taint phenomenon that results from high concentrations of steroids such as androstenone. This topic is also examined in this review. Full article

(This article belongs to the Special Issue Xenobiotic Metabolism)

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2106 KiB

Open AccessTechnical Note

A Computational Drug Metabolite Detection Using the Stable Isotopic Mass-Shift Filtering with High Resolution Mass Spectrometry in Pioglitazone and Flurbiprofen

by Masashi Uchida, Mitsuhiro Kanazawa, Atsushi Ogiwara, Hiroshi Sezaki, Akihiro Ando and Yohei Miyamoto

Int. J. Mol. Sci. 2013, 14(10), 19716-19730; https://doi.org/10.3390/ijms141019716 - 30 Sep 2013

Cited by 3 | Viewed by 7182

Abstract

The identification of metabolites in drug discovery is important. At present, radioisotopes and mass spectrometry are both widely used. However, rapid and comprehensive identification is still laborious and difficult. In this study, we developed new analytical software and employed a stable isotope as a tool to identify drug metabolites using mass spectrometry. A deuterium-labeled compound and non-labeled compound were both metabolized in human liver microsomes and analyzed by liquid chromatography/time-of-flight mass spectrometry (LC-TOF-MS). We computationally aligned two different MS data sets and filtered ions having a specific mass-shift equal to masses of labeled isotopes between those data using our own software. For pioglitazone and flurbiprofen, eight and four metabolites, respectively, were identified with calculations of mass and formulas and chemical structural fragmentation analysis. With high resolution MS, the approach became more accurate. The approach detected two unexpected metabolites in pioglitazone, i.e., the hydroxypropanamide form and the aldehyde hydrolysis form, which other approaches such as metabolite-biotransformation list matching and mass defect filtering could not detect. We demonstrated that the approach using computational alignment and stable isotopic mass-shift filtering has the ability to identify drug metabolites and is useful in drug discovery. Full article

(This article belongs to the Special Issue Xenobiotic Metabolism)

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225 KiB

Open AccessBrief Report

Influence of Genetic Variations on Levels of Inflammatory Markers of Healthy Subjects at Baseline and One Week after Clopidogrel Therapy; Results of a Preliminary Study

by Payman Shahabi, Gérard Siest, Bernard Herbeth, Daniel Lambert, Christine Masson, Jean-Sébastien Hulot, Sébastien Bertil, Pascale Gaussem and Sophie Visvikis-Siest

Int. J. Mol. Sci. 2013, 14(8), 16402-16413; https://doi.org/10.3390/ijms140816402 - 8 Aug 2013

Cited by 3 | Viewed by 5883

Abstract

We aimed to assess the association between the most common polymorphisms of cytochrome P450 (CYP) epoxygenases on the plasma levels of inflammatory markers in a population of healthy subjects. We also sought to determine whether CYP2C19*2 polymorphism is associated with the anti-inflammatory response to clopidogrel. In a population of 49 healthy young males, the baseline plasma levels of inflammatory markers including C-reactive protein, haptoglobin, orosomucoid acid, CD-40 were compared in carriers vs. non-carriers of the most frequent CYP epoxygenase polymorphisms: CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C8*2 and CYP2J2*7. Also, the variation of inflammatory markers from baseline to 7 days after administration of 75 mg per day of clopidogrel were compared in carriers vs. non-carriers of CYP2C19* allele and also in responders vs. hypo-responders to clopidogrel, determined by platelet reactivity tests. There was no significant association between epoxygenase polymorphisms and the baseline levels of inflammatory markers. Likewise, CYP2C19* allele was not associated with anti-inflammatory response to clopidogrel. Our findings did not support the notion that the genetic variations of CYP epoxygenases are associated with the level of inflammatory markers. Moreover, our results did not support the hypothesis that CYP2C19*2 polymorphism is associated with the variability in response to the anti-inflammatory properties of clopidogrel. Full article

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