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Metabolites
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Biochemical Activation and Functions of Drug-Metabolizing Enzymes
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Biochemical Activation and Functions of Drug-Metabolizing Enzymes

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (15 May 2023) | Viewed by 13661

Special Issue Editors

Dr. Muhammad Sajid Hamid Akash

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Guest Editor
Department of Pharmaceutical Chemistry, Government College University, Faisalabad, Pakistan
Interests: Pharmaceutical Analysis; Biochemical Genetics; Cardiometabolic Disorders; Biochemistry of Drug Metabolizing Enzymes
Dr. Kanwal Rehman

E-Mail Website
Guest Editor
Department of Pharmacy, The Women University, Multan, Pakistan
Interests: natural biogenic compounds; epidemiology; metabolic disorders; environmental pollutants; endocrine disruptors; SNP

Special Issue Information

Dear Colleagues,

Drug-metabolizing enzymes (DMEs) have a significant role in the metabolism and activation of many endogenous and exogenous chemical constituents. Biochemical activation is necessary for inducing the proper biological functions of active molecules. Genetic variations in DMEs at the interindividual level compromise the efficacy and safety of numerous drugs. Nowadays, novel advancements in computational methods and modern techniques are being harnessed for the metabolite identification and understanding metabolic mechanistic pathways and networks. The past few decades have seen several advancements in analytical techniques for the qualitative and quantitative analysis of metabolites, biomarkers, and drug-metabolizing enzymes.

This Special Issue aims to present the latest updates and findings regarding the biological functions of DMEs and their isolation, qualification, quantification, and interpersonal variations. This topic will cover the diseases in which the integrity and functionality of these enzymes are compromised, and will present novel updates or possible solutions to overcome these issues.

Dr. Muhammad Sajid Hamid Akash
Dr. Kanwal Rehman
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug-metabolizing enzymes
  • metabolites
  • biomarkers
  • analytical techniques
  • interpersonal drug-metabolizing enzyme variations
  • enzyme deficiencies
  • inflammatory responses in DMEs
  • oxidative stress in DMEs

Published Papers (7 papers)

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Research

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15 pages, 480 KiB  
Article
The Evaluation of CYP2D6, CYP2C9, CYP2C19, and CYP2B6 Phenoconversion in Post-Mortem Casework: The Challenge of Forensic Toxicogenetics
by Arianna Giorgetti, Sara Amurri, Giulia Fazio, Carla Bini, Laura Anniballi, Filippo Pirani, Guido Pelletti and Susi Pelotti
Metabolites 2023, 13(5), 661; https://doi.org/10.3390/metabo13050661 - 16 May 2023
Cited by 2 | Viewed by 1594
Abstract
In toxicogenetics, an integrative approach including the prediction of phenotype based on post-mortem genotyping of drug-metabolising enzymes might help explain the cause of death (CoD) and manner of death (MoD). The use of concomitant drugs, however, might lead to phenoconversion, a mismatch between [...] Read more.
In toxicogenetics, an integrative approach including the prediction of phenotype based on post-mortem genotyping of drug-metabolising enzymes might help explain the cause of death (CoD) and manner of death (MoD). The use of concomitant drugs, however, might lead to phenoconversion, a mismatch between the phenotype based on the genotype and the metabolic profile actually observed after phenoconversion. The aim of our study was to evaluate the phenoconversion of CYP2D6, CYP2C9, CYP2C19, and CYP2B6 drug-metabolising enzymes in a series of autopsy cases tested positive for drugs that are substrates, inducers, or inhibitors of these enzymes. Our results showed a high rate of phenoconversion for all enzymes and a statistically significant higher frequency of poor and intermediate metabolisers for CYP2D6, CYP2C9, and CYP2C19 after phenoconversion. No association was found between phenotypes and CoD or MoD, suggesting that, although phenoconversion might be useful for a forensic toxicogenetics approach, more research is needed to overcome the challenges arising from the post-mortem setting. Full article
(This article belongs to the Special Issue Biochemical Activation and Functions of Drug-Metabolizing Enzymes)
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18 pages, 3509 KiB  
Article
Nanosuspension of Foeniculum Vulgare Promotes Accelerated Sensory and Motor Function Recovery after Sciatic Nerve Injury
by Majed A. Bajaber, Ghulam Hussain, Tahir Farooq, Razia Noreen, Muhammad Ibrahim, Huma Umbreen, Shaheera Batool, Kanwal Rehman, Arruje Hameed, Muhammad Fayyaz Farid and Tanzeela Khalid
Metabolites 2023, 13(3), 391; https://doi.org/10.3390/metabo13030391 - 07 Mar 2023
Cited by 1 | Viewed by 1578
Abstract
The seed extract of Foeniculum vulgare (FV) was used for the preparation of a nanosuspension (NS) with an enhanced bioavailability of phytoconstituents. Subsequently, it was employed as a potent source of polyphenols, such as quercetin and kaempferol, to accelerate the regeneration and recovery [...] Read more.
The seed extract of Foeniculum vulgare (FV) was used for the preparation of a nanosuspension (NS) with an enhanced bioavailability of phytoconstituents. Subsequently, it was employed as a potent source of polyphenols, such as quercetin and kaempferol, to accelerate the regeneration and recovery of motor and sensory function in injured nerves. The NS was administered through daily gauging as NS1 (0.5 mg/mL) and NS2 (15 mg/mL), at a dose rate of 2 g/kg body weight until the end of the study. The NS-mediated retrieval of motor functions was studied by evaluating muscle grip strength and the sciatic functional index. The recovery of sensory functions was assessed by the hotplate test. Several well-integrated biochemical pathways mediate the recovery of function and the regeneration of nerves under controlled blood glucose and oxidative stress. Consequently, the NS-treated groups were screened for blood glucose, total antioxidant capacity (TAC), and total oxidant status (TOS) compared to the control. The NS administration showed a significant potential to enhance the recuperation of motor and sensory functions. Moreover, the oxidative stress was kept under check as a result of NS treatments to facilitate neuronal generation. Thus, the nanoformulation of FV with polyphenolic contents accelerated the reclamation of motor and sensory function after nerve lesion. Full article
(This article belongs to the Special Issue Biochemical Activation and Functions of Drug-Metabolizing Enzymes)
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16 pages, 3502 KiB  
Article
Biochemical Association of MTHFR C677T Polymorphism with Myocardial Infarction in the Presence of Diabetes Mellitus as a Risk Factor
by Tauqeer Hussain Mallhi, Momina Shahid, Kanwal Rehman, Yusra Habib Khan, Abdullah Salah Alanazi, Nasser Hadal Alotaibi, Muhammad Sajid Hamid Akash and Muhammad Hammad Butt
Metabolites 2023, 13(2), 251; https://doi.org/10.3390/metabo13020251 - 09 Feb 2023
Cited by 4 | Viewed by 2236
Abstract
Myocardial infarction (MI) is a cardiovascular disease that occurs due to the blockage of the coronary artery. Subsequently, cardiac muscles receive a lower oxygen supply, which leads to the death of cardiac muscles. The etiology of MI is linked to various environmental, occupational, [...] Read more.
Myocardial infarction (MI) is a cardiovascular disease that occurs due to the blockage of the coronary artery. Subsequently, cardiac muscles receive a lower oxygen supply, which leads to the death of cardiac muscles. The etiology of MI is linked to various environmental, occupational, and genetic factors. Various studies have been conducted on the polymorphism of genes involved in MI. Previous studies have shown that different variants of the methylene tetrahydrofolate reductase (MTHFR) gene are involved in causing MI by altering the metabolism of folate and homocysteine. However, the genetic polymorphism of MTHFR C677T (rs1801133) and its association with MI in the presence of diabetes mellitus (DM) as a risk factor still needs to be investigated. This study recruited 300 participants who were divided into three groups, i.e., the control, MI, and MI-DM. The blood samples collected from the study participants were subjected to various biochemical tests and their clinical parameters were monitored. MTHFR C677T (rs1801133) genotyping was performed by Tetra ARMS PCR using predetermined primers. The MTHFR C677T (rs1801133) polymorphism was associated with MI in the presence of DM as a risk factor among the participants. The MTHFR C677T (rs1801133) T/T homozygous genotype was found to be significant among MI patients in the presence of DM as a risk factor. Full article
(This article belongs to the Special Issue Biochemical Activation and Functions of Drug-Metabolizing Enzymes)
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13 pages, 9904 KiB  
Article
Metabolites of Moringa oleifera Activate Physio-Biochemical Pathways for an Accelerated Functional Recovery after Sciatic Nerve Crush Injury in Mice
by Muhammad Imran, Ghulam Hussain, Arruje Hameed, Iqra Iftikhar, Muhammad Ibrahim, Rahat Asghar, Izzat Nisar, Tahir Farooq, Tanzila Khalid, Kanwal Rehman and Mohammed A. Assiri
Metabolites 2022, 12(12), 1242; https://doi.org/10.3390/metabo12121242 - 09 Dec 2022
Cited by 4 | Viewed by 1292
Abstract
In this study, the functional metabolites of Moringa oleifera (MO) were screened to evaluate their possible role in accelerated functional retrieval after peripheral nerve injury (PNI). MO leaves were used for extract preparation using solvents of different polarities. Each dry extract [...] Read more.
In this study, the functional metabolites of Moringa oleifera (MO) were screened to evaluate their possible role in accelerated functional retrieval after peripheral nerve injury (PNI). MO leaves were used for extract preparation using solvents of different polarities. Each dry extract was uniformly mixed in rodents’ chow and supplemented daily at a dose rate of 2 g/kg body weight from the day of nerve crush until the completion of the trial. The sciatic functional index (SFI) and muscle grip strength were performed to assess the recovery of motor functions, whereas the hotplate test was performed to measure the regain of sensory functions. An optimal level of oxidative stress and a controlled glycemic level mediates a number of physio-biochemical pathways for the smooth progression of the regeneration process. Therefore, total oxidant status (TOS), total antioxidant capacity (TAC) and glycemic levels were analyzed in metabolite-enriched extract-treated groups compared to the control. The supplementation of polar extracts demonstrated a significantly high potential to induce the retrieval of sensory and motor functions. Further, they were highly effective in controlling oxidative stress, facilitating accelerated nerve generation. This study has highlighted MO as a sustainable source of nutritive metabolites and a valuable target for drug development. Full article
(This article belongs to the Special Issue Biochemical Activation and Functions of Drug-Metabolizing Enzymes)
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11 pages, 1990 KiB  
Article
Evaluation of the Association between Single Nucleotide Polymorphisms of Metabolizing Enzymes with the Serum Concentration of Paracetamol and Its Metabolites
by Kannan Sridharan, Ali Mohamed Qader, Mustafa Hammad, Anfal Jassim, Diab Eltayeb Diab, Betsy Abraham, Hasan M. S. N. Hasan, Sheikh Abdul Azeez Pasha and Shamik Shah
Metabolites 2022, 12(12), 1235; https://doi.org/10.3390/metabo12121235 - 09 Dec 2022
Cited by 3 | Viewed by 1468
Abstract
Intravenous paracetamol is a commonly administered analgesic and antipyretic in inpatient settings. Paracetamol is metabolized by cytochrome P450 (CYP) enzymes followed by conjugating enzymes to mainly glucuronide but to a lesser extent, sulphate metabolites, and oxidative metabolites. Single nucleotide polymorphisms (SNPs) in the [...] Read more.
Intravenous paracetamol is a commonly administered analgesic and antipyretic in inpatient settings. Paracetamol is metabolized by cytochrome P450 (CYP) enzymes followed by conjugating enzymes to mainly glucuronide but to a lesser extent, sulphate metabolites, and oxidative metabolites. Single nucleotide polymorphisms (SNPs) in the CYP enzymes result in modified enzymatic activity. The present study was carried out to evaluate the prevalence of SNPs related to paracetamol metabolism and principal metabolites in critically ill patients, and those with chronic kidney disease. The present study is a cross-sectional study carried out in adults (>21 years) requiring intravenous paracetamol as part of their standard of care. Details regarding their demographics, and renal and liver function tests were collected. Blood was withdrawn for the analysis of paracetamol and their metabolites, and the SNPs of key CYP enzymes. Paracetamol/paracetamol glucuronide (P/PG), paracetamol/paracetamol sulphate (P/PS) and PG/PS were estimated. Acute liver injury (ALI) and renal dysfunction were defined using standard definitions. We observed a significant prevalence of SNPs in CYP1A2*1C, CYP3A4*3, CYP1A2*1K, CYP1A2*6, CYP2D6*10, and CYP2E1*2 amongst the 150 study participants. Those with CYP1A2*6 (CC genotype) were observed with significantly lower PG and PS concentrations, and a higher P/PS ratio; CYP2D6*10 (1/1 genotype) with a significantly lower PG concentration and a higher P/PG ratio; and CYP1A2*1K (CC genotype) was observed with a significantly higher PG/PS ratio. Good predictive accuracies were observed for determining the SNPs with the cut-off concentration of 0.29 μM for PS in determining CYP1A2*1K, 0.39 μM for PG and 0.32 μM for PS in determining CYP1A2*6 genotype, and 0.29 μM for PG in determining the CYP2D6*10 genotype. Patients with renal dysfunction were observed with significantly greater concentrations of paracetamol, PG and P/PS, and PG/PS ratios, with a lower concentration of PS. No significant differences were observed in any of the metabolites or metabolite ratios in patients with ALI. We have elucidated the prevalence of key CYP enzymes involved in acetaminophen metabolism in our population. Alterations in the metabolite concentrations and metabolic ratios were observed with SNPs, and in patients with renal dysfunction. Population toxicokinetic studies elucidating the dose-response relationship are essential to understand the optimized dose in this sub-population. Full article
(This article belongs to the Special Issue Biochemical Activation and Functions of Drug-Metabolizing Enzymes)
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Review

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15 pages, 1441 KiB  
Review
Biochemical Activation and Regulatory Functions of Trans-Regulatory KLF14 and Its Association with Genetic Polymorphisms
by Muhammad Sajid Hamid Akash, Sumbal Rasheed, Kanwal Rehman, Muhammad Ibrahim, Muhammad Imran and Mohammed A. Assiri
Metabolites 2023, 13(2), 199; https://doi.org/10.3390/metabo13020199 - 29 Jan 2023
Viewed by 1830
Abstract
Krüpple-Like family of transcription factor-14 (KLF14) is a master trans-regulatory gene that has multiple biological regulatory functions and is involved in many pathological mechanisms. It controls the expressions of several other genes which are involved in multiple regulatory functions. KLF14 plays a significant [...] Read more.
Krüpple-Like family of transcription factor-14 (KLF14) is a master trans-regulatory gene that has multiple biological regulatory functions and is involved in many pathological mechanisms. It controls the expressions of several other genes which are involved in multiple regulatory functions. KLF14 plays a significant role in lipid metabolism, glucose regulation and insulin sensitivity. Cell apoptosis, proliferation, and differentiation are regulated by the KLF14 gene, and up-regulation of KLF14 prevents cancer progression. KLF14 has been used as an epigenetic biomarker for the estimation of chronological age due to the presence of different age-related CpG sites on genes that become methylated with age. Different genome-wide association studies have identified several KLF14 variants in adipose tissues. These single nucleotide polymorphisms in KLF14 have been associated with dyslipidemia, insulin resistance, and glucose intolerance. Moreover, the prevalence of genetic polymorphism is different in different populations due to ethnic differences and epigenetic modifications. In addition, environmental and physiological factors such as diet, age, gender, and obesity are also responsible for genetic mutations in KLF14. Full article
(This article belongs to the Special Issue Biochemical Activation and Functions of Drug-Metabolizing Enzymes)
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14 pages, 926 KiB  
Review
Genetic Polymorphism in Angiotensinogen and Its Association with Cardiometabolic Diseases
by Momina Shahid, Kanwal Rehman, Muhammad Sajid Hamid Akash, Shaleem Suhail, Shagufta Kamal, Muhammad Imran and Mohammed A. Assiri
Metabolites 2022, 12(12), 1291; https://doi.org/10.3390/metabo12121291 - 19 Dec 2022
Cited by 11 | Viewed by 2552
Abstract
Angiotensinogen (AGT) is one of the most significant enzymes of the renin-angiotensin-aldosterone system (RAAS) which is involved in the regulation and maintenance of blood pressure. AGT is involved in the production of angiotensin I which is then converted into angiotensin II that leads [...] Read more.
Angiotensinogen (AGT) is one of the most significant enzymes of the renin-angiotensin-aldosterone system (RAAS) which is involved in the regulation and maintenance of blood pressure. AGT is involved in the production of angiotensin I which is then converted into angiotensin II that leads to renal homeostasis. However, various genetic polymorphisms in AGT have been discovered in recent times which have shown an association with various diseases. Genetic polymorphism increases the level of circulating AGT in blood which exaggerates the effects produced by AGT. The associated diseases occur due to various effects produced by increased AGT levels. Several cardiovascular diseases including myocardial infarction, coronary heart disease, heart failure, hypertrophy, etc. are associated with AGT polymorphism. Other diseases such as depression, obesity, diabetic nephropathy, pre-eclampsia, and liver injury are also associated with some variants of AGT gene. The most common variants of AGT polymorphism are M235T and T174M. The two variants are associated with many diseases. Some other variants such as G-217A, A-6G, A-20C and G-152A, are also present but they are not as significant as that of M235T and T174M variants. These variants increase the level of circulating AGT and are associated with prevalence of different diseases. These diseases occur through various pathological pathways, but the initial reason remains the same, i.e., increased level of AGT in the blood. In this article, we have majorly focused on how genetic polymorphism of different variants of AGT gene is associated with the prevalence of different diseases. Full article
(This article belongs to the Special Issue Biochemical Activation and Functions of Drug-Metabolizing Enzymes)
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