Current Drug Metabolism - Volume 17, Issue 4, 2016

Solid tumors account for approximately 30% of all pediatric cancers. Although chemotherapy has largely contributed to strongly improve patient outcome, multidrug resistance (MDR) remains one of the major mechanisms limiting the overall survival. The enhanced efflux rate of chemotherapeutic drugs from tumor cells through drug transporters is one of the most important mechanisms of MDR. Drug transporters play a pivotal role in preserving the balance between sensitivity and resistance of tumor cells to anti-neoplastic drugs. Their functional activities have been barely investigated in pediatric solid malignancies. Here, we provide evidence from the current literatures on drug transporters and MDR in the most common types of pediatric solid tumors, including neuroblastoma, Wilms’ tumor, rhabdomyosarcoma, retinoblastoma, medulloblastoma and hepatoblastoma.

Background: Acrylamide (AA), a known neurotoxin, has been considered to be a probable human carcinogen. The discovery of AA in many common foods in 2002 has caused worldwide attention and led to numerous research efforts on the metabolism of AA. Methods: By collecting research literatures related to metabolism of AA, the present review not only summarized the major metabolic pathways and enzymes of AA, but also compared the interindividual and the interspecies differences of AA metabolism among humans, rats and mice. Moreover, the application of the metabolites as biomarkers for the AA exposure assessment in human population was also discussed. Results: The interindividual differences of AA metabolism may be attributed to the activity and/or genetic polymorphisms of metabolic enzymes in individuals with different gender, age, smoking and alcohol status. Moreover, the metabolism of AA in humans may be more prone to the phase II conjugation with glutathione (GSH) than the phase I conversion of AA to glycidamide (GA) when compared with rats and mice. Both the hemoglobin (Hb) adducts and urinary mercapturic acid (MA) metabolites have been successfully used as biomarkers for the risk assessment of AA and new metabolic biomarkers are being developed. Conclusion: The genotoxic risk from AA may be determined by the balance between the phase I P450 2E1 (CYP2E1)-dependent toxification pathway to form genotoxic GA and the phase II GSH-conjugated detoxification pathway to form MA metabolite. Understanding the metabolism of AA in the body is helpful for developing effective intervention strategies to mitigate its toxicity.

Background: It is well known that ethanol can cause significant morbidity and mortality, and much of the related toxic effects can be explained by its metabolic profile. Objective: This work performs a complete review of the metabolism of ethanol focusing on both major and minor metabolites. Method: An exhaustive literature search was carried out using textual and structural queries for ethanol and related known metabolizing enzymes and metabolites. Results: The main pathway of metabolism is catalyzed by cytosolic alcohol dehydrogenase, which exhibits multiple isoenzymes and genetic polymorphisms with clinical and forensic implications. Another two oxidative routes, the highly inducible CYP2E1 system and peroxisomal catalase may acquire relevance under specific circumstances. In addition to oxidative metabolism, ethanol also originates minor metabolites such as ethyl glucuronide, ethyl sulfate, ethyl phosphate, ethyl nitrite, phosphatidylethanol and fatty acid ethyl esters. These metabolites represent alternative biomarkers since they can be detected several hours or days after ethanol exposure. Conclusion: It is expected that knowing the metabolomics of ethanol may provide additional insights to better understand the toxicological effects and the variability of dose response.

Background: Neuropathic pain is an incurable disease which is defined as a chronic pain caused by a disease or lesion of the nervous systems. Current treatments can provide a long-lasting pain relief only in a very limited number of patients with neuropathic pain. MicroRNA can regulate multiple genes and pathways involved in human diseases. This review focuses on: a) Molecular mechanisms of microRNA biogenesis. b) Targeting, modifications, and delivery of microRNAs. c) Aberrant expression of microRNAs and their potential therapeutic targets in neuropathic pain. d) Potential challenges of microRNA therapy in clinical practice, such as off-target effects, toxicity, delivery hurdles, and target prediction. Results: This review introduces: 1. Canonical/non-canonical pathway of microRNA biogenesis. 2. Viral/non-viral vectors transporting microRNAs into target cells. 3. MicroRNA mimics/inhibitors targeting strategies. 4. Aberrantly expressed microRNAs in different animal neuropathic pain models and their links to underlying mechanisms such as inflammation and ion channel expression. 5. Potential challenges of microRNAs therapy such as off-target effect, pseudogenes, liver toxicity, delivery hurdles and target prediction. Conclusion: Although using microRNAs to target neuropathic pain seem promising, their off-target/toxic effects and delivery hurdles still need to be surmounted.

Objective: Coenzyme Q10 (CoQ10) is an endogenous lipid-soluble benzoquinone compound that functions as a diffusible electron carrier in the electron transport chain. It is prevalent in all human tissues and organs, although it is mainly biosynthesised and concentrated in tissues with high energy turnover. The aim of this review was to perform an exhaustive analysis of the influence and effects of CoQ10 supplementation on parameters related to exercise in healthy humans, and to clarify the current state of knowledge of this field of study, presenting the relevant data in a systematic manner. Method: This paper describes a transversal descriptive systematic review of published research in this field; the study was conducted using a method adapted from the PRISMA guidelines. The inclusion criteria applied were based on the PICO (population, intervention, comparison, and outcome) model. Results: The database search performed yielded 372 citations. Finally, 13 studies met all the inclusion criteria and were incorporated in the present review. Conclusion: CoQ10 has properties related to bioenergetic and antioxidant activity; thus, it is intimately involved in energy production and in the prevention of peroxidative damage to membrane phospholipids and of free radical-induced oxidation. These properties make it suitable as a dietary supplement to improve cellular bioenergetics and to inhibit certain age-related pathologies.

Background: Diabetes mellitus (DM) is a pandemic metabolic disease characterized by a chronically elevated blood glucose concentration (hyperglycemia) due to insulin dysfunction. Approximately 50% of diabetics show diabetes complications by the time they are diagnosed. Vascular dysfunction, nephropathy and neuropathic pain are common diabetes complications. Chronic hyperglycemia contributes to reactive oxygen species (ROS) generation such as methylglyoxal (MGO). Methods: Peer reviewed research papers were studied through bibliographic databases searching focused on review questions and inclusion/exclusion criteria. The reviewed papers were appraised according to the searching focus. The characteristics of screened papers were described, and a deductive qualitative content analysis methodology was applied to the included studies using a conceptual framework to yield this comprehensive systematic review. Results: Sixty-six papers were included in this review. Eleven papers related methylglyoxal generation to carbohydrates metabolism, ten papers related lipid metabolism to methylglyoxal and 5 papers showed the proteolytic pathways that contribute to methylglyoxal generation. Methylglyoxal metabolism was derived from 7 papers. Descriptive figure 1 was drawn to explain methylglyoxal sources and how diabetes increases methylglyoxal generation. Furthermore, twenty-six papers related methylglyoxal to diabetes complications from which 9 papers showed methylglyoxal ability to induce insulin dysfunction, an effect which was described in schematic figure 2. Additionally, fifteen papers revealed methylglyoxal contribution to vascular dysfunction and 3 papers showed methylglyoxal to cause neuropathic pain. Methylglyoxal-induced vascular dysfunction was drawn in a comprehensive figure 3. This review correlated methylglyoxal with diabetes and diabetes complications which were summarised in table 1. Conclusion: The findings of this review suggesting methylglyoxal as an essential therapeutic target for managing diabetes in the future.

Background: Reactive species have been regarded as by-products of cellular metabolism, which cause oxidative damage contributing to aging and neurodegenerative diseases. However, accumulated evidence support the notion that reactive species mediate intracellular and extracellular signals that regulate physiological functions including posttranslational protein modifications. Cysteine thiol groups of proteins are particularly susceptible to oxidative modifications by oxygen, nitrogen and sulfur species generating different products with critical roles in the cellular redox homeostasis. At physiological conditions, reactive species can function not only as intracellular second messengers with regulatory roles in many cellular metabolic processes but also as part of an ancestral biochemical network that controls cellular survival, regeneration, and death. Objective: To propose a biochemical network, called cellular cysteine network (CYSTEINET), which can be dysregulated in Parkinson’s disease. Due to the fact that there are many cysteine-bearing proteins and cysteine-dependent enzymes susceptible to oxidative modifications, it is proposed that oxidative-changed proteins at cysteine residues may be critical for Parkinson’s disease development. Conclusion: In the present review, I advance the concept that “cysteinet” is impaired in Parkinson’s disease resulting in a functional and structural dysregulation of the matrix of interconnected cysteine-bearing proteins, which in conjunction with reactive species and glutathione regulate the cellular bioenergetic metabolism, the redox homeostasis, and the cellular survival. This network may represent an ancestral down-top system composed of a complex matrix of proteins with very different cellular functions, but bearing the same regulatory thiol radical. Finally, the possible role of N-acetylcysteine and derivatives to regulate “cysteinet” and slow down Parkinson’s disease development and progression is discussed.

Background: During the development, dosage optimization and safety evaluation of a drug, rapid and precise monitoring of an administered drug and/or its metabolites in biological samples. As drug biotransformation produces more hydrophilic metabolites for the enhancement of drug elimination, it often presents a challenge for traditional reversed-phase liquid chromatography (RPLC) separation. Because hydrophilic interaction liquid chromatography (HILIC) is capable of retaining polar compounds and is readily compatible with mass spectrometry (MS), HILIC has been used as a complementary separation technique to RPLC for the analysis of polar metabolites, especially polar drugs and their metabolites. Methods: We undertook a comprehensive search of databases for HILIC-related research literature. The characteristics including method, result and innovation of screened papers were described, and an inductive and analytical method was applied to analyze those studies using a reasonable framework. Results: This paper covers core aspects of the HILIC-MS/MS method and the overall profile of its application in drug and/or its metabolites analysis by reviewing 102 papers. The emphasis of this paper has been placed on the applications of the HILIC-MS/MS method in quantitative bioanalysis of drugs alone or along with their metabolites in drug metabolism studies in recent years. As a fundamental and critical step of the bioanalytical method, conventional sample preparation techniques of biological matrices for the HILIC-MS/MS analysis of drugs and/or their metabolites are also briefly featured. Conclusion: The findings of this review confirm the powder of HILIC-MS/MS methods in the separation and quantification of drugs and/or their metabolites.

Background: Indoles, including indole-3-carbinol (I3C) and its derivatives, are the products of glucosinolate hydrolysis catalyzed by the enzyme myrosinase. Under acidic conditions, I3C polymerizes into 3, 3- diindolylmethane (DIM), [2-(indol-3-ylmethyl)-indol-3-yl]indol-3-ylmethane (LTr1), 1-(3-hydroxymethyl)- indolyl-3-indolylmethane (HI-IM) and indolo[3,2b]carbazole (ICZ). Recently, I3C and its dimer DIM have shown pleiotropic protective effects on chronic liver injuries, including viral hepatitis, hepatic steatosis, hepatic cirrhosis, hepatocellular carcinoma, and so on. Methods: We reviewed the published papers about the pharmacokinetics of I3C and its derivatives in vitro and in vivo, and summarized their multiple protective roles in the processes of chronic liver diseases. Results: Indoles not only regulate transcriptional factors and their respective signaling pathways, but also relieve oxidative stress and inhibit the synthesis of DNA to influence the activation, proliferation and apoptosis of target cells. Moreover, indoles modulate the enzymes that are relevant to hepatitis viral replication, lipogenesis, and the metabolism of ethanol and some hepatotoxic substances to protect the liver. Currently, the immunomodulatory biofunction of indoles contributes to improving non-alcoholic steatohepatitis. In addition, indoles also function as the inhibitors of pro-inflammatory cytokines and chemokines to reduce microbial-induced liver injures. Conclusion: Indoles, especially I3C and DIM as phytochemicals, exert anti-fibrosis, anti-tumor, anti-oxidant, immunomodulatory, detoxification and anti-inflammation effects on hepatic protection through pleiotropic mechanism.