Current Drug Metabolism (v.17, #6)

Meet Our Editorial Board Member by J. Matthew Hutzler (519-519).

A Comparison of Non-Human Primate Cytochrome P450 2D Members and the Implication in Drug Discovery by Zhi-Xu He, Xiao-Wu Chen, Yinxue Yang, Shu-Feng Zhou (520-527).
Background: Non-human primates are valuable animal models in drug discovery and biomedical research. Human CYP2D6 accounts for 1.3-4.3% of total hepatic CYP content in the liver, but is involved in the metabolism of more than 150 drugs. With the advancement of genomic sequencing and annotation, a panel of CYP2D genes have been cloned from non-human primates. This review highlights the similarities and differences of these CYP2D genes non-human primates.
Methods: We conducted a structured PubMed search using a focused review question and proper inclusion/exclusion criteria. The quality of retrieved papers was assessed and briefed using standard tools and expert knowledge.
Results: Most studies on CYP expression in non-human primates have been carried out in the cynomolgus and Rhesus monkeys. Deduced amino acid sequences of primate CYP2D cDNAs share high sequence identity (93-96%) with human CYP2D6. The chimpanzee genome has CYP2D6 and 2D7 but bonobos only contain CYP2D6. The CYP2D6 gene is located on chromosome 22 in the chimpanzee genome (human CYP2D6 maps to chromosome 22q13.1), and on chromosome 10 in the genome of the Rhesus monkey. Cynomolgus monkey CYP2D17 and Japanese monkey 2D29 metabolize bufuralol and dextromethorphan. CYP2D17 metabolizes bufuralol and dextromethorphan, whereas CYP2D29 metabolizes bufuralol and debrisoquine. In addition, quinidine inhibits both cynomolgus monkey CYP2D17 and Japanese monkey 2D29.
Conclusion: The CYP2D members from non-human primates show differential genomic contexts, catalytic activities toward substrates and inhibitory profiles. Further studies are warranted to elucidate the structural and functional features of CYP2D members in non-human primates and thus offer a solid base for the application of these animals in drug discovery.

Background: Sulfotransferase (SULT) 1A1 is a phase II metabolic enzyme that catalyzes sulfate conjugation of various phenolic compounds, including endogenous substances, such as estrogens and thyroid hormones, but also different xenobiotics. Although sulfation is classically considered as a detoxification event facilitating the excretion of more water soluble metabolites from the body, in some cases such bioconversion may also lead to bioactivation of promutagens, producing highly reactive intermediates which are capable of damaging DNA and promoting carcinogenesis. The most common polymorphism in SULT1A1 (Arg213His) has an important functional impact by affecting the capacity to sulfate diverse substrates and numerous case-control studies have shown associations between SULT1A1 variants and susceptibility to different malignancies. Several factors may significantly influence such relationships, including ethnicity, gender, parity, menopausal status, use of estrogen replacement therapy, exposure to tobacco smoke or occupational chemicals.
Results and Conclusion: In this review article, we show that one more important determinant should be considered as a stratifying factor in studies of possible associations between SULT1A1 variants and cancer risk, i.e., the dietary intake of different flavonoids. As sulfation of bioactive plant polyphenols can change their potential anticancer activities and, on the other hand, these phytochemicals are capable to behave also as potent SULT1A1 inhibitors, the regular dietary exposure of humans to these compounds can make a great contribution to the impact of sulfation capacity on individual susceptibility to carcinogenesis. The effect of specific flavonoids as well as their interactions with other factors on associations between SULT1A1 alleles and cancer risk certainly needs further thorough studies..

Thiopurine Biotransformation and Pharmacological Effects: Contribution of Oxidative Stress by Marco Pelin, Sara De Iudicibus, Margherita Londero, Riccardo Spizzo, Sveva Dei Rossi, Stefano Martelossi, Alessandro Ventura, Giuliana Decorti, Gabriele Stocco (542-549).
Background: Thiopurine antimetabolites are important agents for the treatment of severe diseases, such as acute lymphoblastic leukemia and inflammatory bowel disease. Their pharmacological actions depend on biotransformation into active thioguanine-nucleotides; intracellular metabolism is mediated by enzymes of the salvage pathway of nucleotide synthesis and relies on polymorphic enzymes involved in thiopurines' catabolism such as thiopurine-S-methyl transferase. Given the enzymes involved in thiopurines' metabolism, it is reasonable to hypothesize that these drugs are able to induce significant oxidative stress conditions, possibly altering their pharmacological activity.
Methods: A systemic search of peer-reviewed scientific literature in bibliographic databases has been carried out. Both clinical and preclinical studies as well as mechanistic studies have been included to shed light on the role of oxidative stress in thiopurines' pharmacological effects.
Results: Sixty-nine papers were included in our review, allowing us to review the contribution of oxidative stress in the pharmacological action of thiopurines. Thiopurines are catabolized in the liver by xanthine oxidase, with potential production of reactive oxidative species and azathioprine is converted into mercaptopurine by a reaction with reduced glutathione, that, in some tissues, may be facilitated by glutathione- S-transferase (GST). A clear role of GSTM1 in modulating azathioprine cytotoxicity, with a close dependency on superoxide anion production, has been recently demonstrated. Interestingly, recent genome-wide association studies have shown that, for both azathioprine in inflammatory bowel disease and mercaptopurine in acute lymphoblastic leukemia, treatment effects on patients' white blood cells are related to variants of a gene, NUDT15, involved in biotransformation of oxidated nucleotides.
Conclusions: Basing on previous evidences published in literature, oxidative stress may contribute to thiopurine effects in significant ways that, however, are still not completely elucidated.

Pharmacological Effects of RAAS Blockade in Ischemic Nephropathy by Laura Rivoli, Francesca Di Mario, Giuseppe Coppolino, Antonietta Gigante, Biagio Barbano, Tariq E. Farrah, Edoardo Rosato, Giorgio Fuiano, Rosario Cianci (550-558).
Background: The management of ischemic nephropathy due to atherosclerotic renal artery stenosis has become increasingly conservative in the modern era, with current guidelines recommending optimized medical therapy as the initial step. The doubts raised by the recently published trials of revascularization strategies have led to a renewed focus on pharmacological strategies promoting blood pressure control and renal protection. It is essential to further elucidate the pathophysiological mechanisms underlying hypoperfusion induced renal microvascular dysfunction with subsequent tissue injury and fibrogenesis. The role of renin angiotensin aldosterone system as a mediator of the main pathophysiological consequences of ischemic nephropathy is well known. However, more recent experimental evidence on the adrenergic system and intrarenal tubular feedback mechanisms has stimulated new interest towards a multi-target therapeutic approach.
Methods: This review focuses on the pharmacology of the principle therapeutic drug classes currently used in the treatment of atherosclerotic renal artery stenosis with an analysis of their metabolic aspects and use in clinical practice based on evidence from clinical trials.
Results and Conclusions: An optimal pharmacologic approach is crucial for a successful prevention of renal injury and cardiovascular events in this high-risk population. Antihypertensive treatment should include renin angiotensin aldosterone system blockade medication not only for their antihypertensive properties, but especially for those cardio and renoprotective.

Effects of High Altitude Exposure on Physiology and Pharmacokinetics by Lu Hui, Wang Rong, Jia Zheng-ping, Xiong Juan, Xie Hua (559-565).
Background: High-altitude environments are known to result in a broad range of physiological changes in human body, which may influence various pharmacological processes and pharmacokinetics. A series of physiological systems reacting to a high-altitude stressor and the effects of these physiological alterations on pharmacokinetics have been investigated for decades.
Methods: In this review, we summarized the effects of high altitude on human physiological alterations (including those in the gastrointestinal system, cardiovascular system, pulmonary system, hematocrit, drug metabolism enzyme system, and renal excretory system), as well as subsequent changes of pharmacokinetics (such as absorption, distribution, metabolism, and excretion of drugs).
Results: In summary, it isclear that high altitudes can lead to a broad range of physiological changes, leading to the changes in the ADME process of drugs.
Conclusion: According to previous pharmacokinetics studies in human, the pharmacokinetics changes due to high altitude exposure may require dosage regimen modifications to maintain drug efficacy and safety, which should draw our attention to drug administration dosage for those planning ascent to high altitudes.

Genomic Variations Affecting Biological Effects of Statins by Alessandra Bitto, Giovanni Pallio, Sonia Messina, Vincenzo Arcoraci, Gabriele Pizzino, Giuseppina T. Russo, Socrate Pallio, Francesco Squadrito, Domenica Altavilla (566-572).
Background: Statins are inhibitors of hydroxy-methyl-glutaryl coenzymeA (HMG-CoA) reductase, the rate-limiting enzyme involved in de novo cholesterol synthesis. The patient health profile needs to be taken in account during the interpretation of the variability in the outcome of drug therapy, as well as compliance with prescribed pharmacological treatments, and genetic profile.
Objective: Several genetic polymorphisms playing a role in the different response to lipid lowering therapy have recently been identified. Statins, today are used to reduce Low Density Lipoprotein-Cholesterol (LDL-C), represent the treatment of choice in individuals with increased risk of Cardio-Vascular Disease (CVD), both in primary and secondary prevention of cardiovascular events. Regardless of the usefulness in a wide range of patients, the common interindividual genetic variability, along with phenotypic aspects, lead to resistance and adverse responses.
Methods: we reviewed on PubMed, inserting as term search “statin and polymorphism”, “statin and pharmacogenomic”, “statin and gene”, “HMG-CoA reductase and gene”.
Results: A large number of candidate genes and many single nucleotide polymorphisms (SNPs) have been evaluated and related to pharmacokinetic and/or pharmacodynamic of statins.
Conclusion: Despite these several findings there is still not enough evidence to recommend pharmacogenomic tests before starting statin therapy.

Valproic Acid Metabolism and its Consequences on Sexual Functions by Alberto Verrotti, Elisabetta Mencaroni, Marta Cofini, Miriam Castagnino, Antonio Leo, Emilio Russo, Vincenzo Belcastro (573-581).
Background: Valproic acid (VPA) is a broad spectrum antiepileptic drug (AED) that is generally regarded as a first-choice agent for most forms of idiopathic and symptomatic generalised epilepsies. Available data suggest that menstrual disorders and certain endocrine manifestations of reproductive system disorders may be more common in women treated with VPA than in those treated with other AEDs.
Methods: A PubMed search for MEDLINE was undertaken to look for studies using the terms “VPA metabolism”, “VPA and sexual functions in men”, “VPA and sexual functions in women” and “VPA metabolism and endocrine disorders” as key words. The period covered was approximately 20 years.
Results: In women, VPA medication is associated with hyperandrogenism, polycystic ovary/polycystic ovarian syndrome, menstrual disorders and ovulatory failure. Men on VPA therapy show abnormalities in androgens blood levels, sperm motility and erectile dysfunctions. VPA negatively affects the release of luteinizing hormone, follicle stimulating hormone and prolactin but also the drug interferes in peripheral endocrine hormones. Its broad inhibitory action on cytochrome and glucuronidation systems can lead to high serum concentration of testosterone, androstenedione and dehydroepiandrosterone sulfate. VPA-dependent obesity and hyperinsulinemia can further contribute to an increase in sexual dysfunctions.
Conclusions: VPA interferes with the endocrine system at multiples levels causing several reproductive and sexual dysfunctions in women and men with epilepsy, especially when administered in pubertal age. Since VPA is a first line AED both in children and adult with epilepsy and long-term medication with this drug is sometimes necessary, it is very important for physicians to implement strict monitoring of patients taking VPA in order to identify these kinds of side effects at an early stage.

Emerging Potential of Natural Products as an Alternative Strategy to Pharmacological Agents Used Against Metabolic Disorders by Tânia R. Dias, Raquel L. Bernardino, Maria J. Meneses, Mário Sousa, Rosália Sá, Marco G. Alves, Branca M. Silva, Pedro F. Oliveira (582-597).
Background: Human metabolism is an essential biological process that involves the consumption of different substrates to ensure the nutritional and energetic needs of cells. The disruption of this highly regulated system constitutes the onset of several disorders/dysfunctions such as diabetes mellitus, cardiovascular diseases and hypertension.
Objective: In this review, we propose to discuss promising natural products that can act as modulators of cell metabolism and point towards possible targets to take into account in the development of new therapies against metabolic diseases.
Methods: After having defined our main focus, we undertook an intensive search of bibliographic databases to select the peer-reviewed papers that fits within the review thematic. The information of the screened papers was described in an organized manner through the review and different types of studies were included.
Results: Two hundred and seventy papers were included in the review, as well as one reliable website from the World Health Organization. Several articles described that pharmacological agents are commonly used to counteract metabolic disorders. However, in many cases these products are insufficient, represent high costs to health care systems and are associated with several undesirable effects, highlighting the need to search for new therapies. Notably, many papers reported the promising results of natural products in the treatment of several metabolic disorders, constituting a possible alternative or complementary strategy to pharmacological agents.
Conclusion: The findings of this review confirm that the currently available treatments for metabolic disorders and its associated complications remain far below the expected results.

Background: Polyphenols are functional compounds in edible vegetable and food such as tea, coffee and red wine and increasing evidence demonstrates a positive link between consumption of polyphenol-rich foods and disease prevention.
Objective: In this review we have focused on the current knowledge of the potential anti-glycation effects of polyphenols, particularly in regard to their influence on Maillard reaction, a non-enzymatic reaction between amino acids and reducing sugars that contributes to the production of toxic compounds, mainly reactive carbonyl species, advanced glycation end-products (AGEs) and other toxicants.
Method And Results: The Maillard reaction occurs in the human body during hyperglycemic condition, but it is well known as browning reaction in thermally processed foods and it is responsible for flavor and toxicant formation. Dietary polyphenols can have anti-glycation effects and actively participate in Maillard reaction, mitigating the AGE formation and the heat-induced production of toxic compounds.
Conclusion: In a time in which the role of a healthy diet in the prevention of chronic diseases is welcome and the borderline between food and medicine is becoming very thin, an improved mechanistic knowledge of how polyphenols can function to reduce harmful and unhealthy substances is mandatory.

Medication-Induced Nephrotoxicity in Older Patients by Sergio Fusco, Sabrina Garasto, Andrea Corsonello, Silvio Vena, Vincenzo Mari, Pietro Gareri, Giovanni Ruotolo, Filippo Luciani, Arturo Roncone, Marcello Maggio, Fabrizia Lattanzio (608-625).
Objective: To summarize current evidence about mechanisms, clinical features, diagnostic issues, and strategies for prevention of medication-induced nephrotoxicity among older people.
Methods: A Pubmed search was performed, and studies concerning age-related changes in kidney structure and function predisposing to nephrotoxicity, pathophysiological mechanisms, kidney drug metabolism enzymes, clinical epidemiology of medication-induced kidney damage, biomarkers for early identification of nephrotoxicity and strategies for prevention of medication-induced nephrotoxicity among older people were selected. Finally, 245 papers were included in the review.
Results: Medications may induce nephrotoxicity through several pathophysiological mechanisms. People aged 75 or more are especially exposed to potential nephrotoxic medications or combinations of medications in the context of complex polypharmacy regimens. Estimated glomerular filtration rate (eGFR) may be useful to identify medication-induced alterations in kidney function, but creatinine-based methods have important limitation in older patients. Several innovative biomarkers have been proposed to identify AKI but these methodologies are not standardized and older people have not been evaluated systematically. Factors related to patient, medication, and interactions should be taken into account for effective prevention.
Conclusions: Medication-induced nephrotoxicity is a relevant problem in older populations. Nevertheless, several areas of uncertainty remain to be explored, including the impact of nephrotoxicity on functional outcomes relevant to older patients, the reliability of currently recommended methods for diagnosing and staging AKI, the use of innovative biomarkers in such a heterogeneous population, the effectiveness of preventing strategies and treatments and their impact on functional outcomes.