Abstract:
:Enormous efforts toward predicting the metabolic fate of a drug have been driven by the high attrition rate in drug development. To accelerate such efforts, it is critical to elucidate the molecular mechanisms of drug recognition by drug-metabolizing enzymes. Therefore, it is not surprising that an increasing number of crystal structures have been determined (by X-ray crystallography) and numerous insightful in silico (computational) models have been established for the most important metabolic enzymes, cytochrome P450s (CYPs). In this review, we provide a detailed analysis of the available crystal structures for CYPs to reveal the structural features and protein flexibility determining substrate selectivity. The ligand-based in silico models (including pharmacophore and molecular field analysis models) are also discussed, with a focus on their ability to characterize the structural features of the substrates for various CYP isoforms.
journal_name
Drug Metab Revjournal_title
Drug metabolism reviewsauthors
Dong D,Wu Bdoi
10.3109/03602532.2011.645581subject
Has Abstractpub_date
2012-02-01 00:00:00pages
1-17issue
1eissn
0360-2532issn
1097-9883journal_volume
44pub_type
杂志文章,评审abstract::The mitochondrial amidoxime-reducing component (mARC) is a recently discovered molybdenum-containing enzyme in mammalians. Upon reconstitution with the electron transport proteins, cytochrome b(5) and its reductase, this molybdenum enzyme is capable of reducing N-hydroxylated compounds. It was named mARC because the N...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.3109/03602532.2011.608682
更新日期:2011-11-01 00:00:00
abstract::The present paper has discussed available test systems for determination of the response of G-6-PD-deficient human erythrocytes to environmental agents. The limitations and advantages of each model have been examined, and the results of research using each model have been presented. The future development of suitable ...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.3109/03602538608998292
更新日期:1986-01-01 00:00:00
abstract::A number of therapeutic drugs with different structures and mechanisms of action have been reported to undergo metabolic activation by Phase I or Phase II drug-metabolizing enzymes. The bioactivation gives rise to reactive metabolites/intermediates, which readily confer covalent binding to various target proteins by n...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.1081/dmr-200028812
更新日期:2005-01-01 00:00:00
abstract::In summary, we have shown that steroid D-ring, but not steroid A-ring, glucuronide conjugates act at the level of the bile canaliculus to decrease bile-acid-dependent flow, initially; and subsequently, bile-acid-independent flow. These data indicate that glucuronide conjugates are not necessarily inactive; the present...
journal_title:Drug metabolism reviews
pub_type: 杂志文章
doi:10.3109/03602538308991419
更新日期:1983-01-01 00:00:00
abstract::For patients undergoing cardiopulmonary bypass (CPB) during cardiac surgery, there are well-documented changes in the pharmacokinetics (PK) of commonly administered drugs. Although multiple factors potentially underpin these changes, there has been scant research attention on the impact of CPB to alter the activities ...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.1080/03602532.2017.1417423
更新日期:2018-05-01 00:00:00
abstract::In this review of the literature on surface-enhanced Raman scattering (SERS), we describe recent developments of this technique in the medical field. SERS has developed rapidly in the last few years as a result of the fascinating advancements in instrumentation and the ability to interpret complex Raman data using hig...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.3109/03602532.2013.873451
更新日期:2014-05-01 00:00:00
abstract::Chemicals that cause toxicity though a direct mechanism, such as acetaminophen, covalently bind to a select group of proteins prior to the development of toxicity, and these proteins may be important in the initiation of the events that lead to the hepatotoxicity. Disruption of the cell is measured by release of intra...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.3109/03602539709037572
更新日期:1997-02-01 00:00:00
abstract::Dehydroepiandrosterone has been thought to have physiological functions other than as an androgen precursor. The previous studies performed have demonstrated a number of biological effects in rodents, such as amelioration of disease in diabetic, chemical carcinogenesis, and obesity models. To date, activation of the p...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.1080/03602530600569877
更新日期:2006-01-01 00:00:00
abstract::Historically, failure rates in drug development are high; increased sophistication and investment throughout the process has shifted the reasons for attrition, but the overall success rates have remained stubbornly and consistently low. Only 8% of new entities entering clinical testing gain regulatory approval, indica...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.1080/03602532.2020.1726944
更新日期:2020-05-01 00:00:00
abstract::Herbert Remmer was a pioneer in the study of the phenomenon of enzyme induction. He was also a leading figure, if not the foremost, in the development of the discipline of toxicology in Germany during his tenure as Professor of Toxicology at the University of Tübingen. Included here are some brief thoughts about where...
journal_title:Drug metabolism reviews
pub_type: 传,历史文章,杂志文章
doi:10.1081/dmr-200033409
更新日期:2004-10-01 00:00:00
abstract::Cytochrome P450 2D6 (CYP2D6) is a polymorphic enzyme responsible for metabolizing approximately 25% of all drugs. CYP2D6 is highly expressed in the brain and plays a role as the major CYP in the metabolism of numerous brain-penetrant drugs, including antipsychotics and antidepressants. CYP2D6 activity and inhibition h...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.3109/03602532.2015.1047026
更新日期:2015-08-01 00:00:00
abstract::This article reviews the regulatory, social, policy, and other issues that will shape the development of pharmacogenomics applications. We identify and analyze 19 key public policy issues, ranging from the economic incentives for linked diagnostic-drug development, to the regulation of tests and drugs, and to privacy ...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.1080/03602530801952500
更新日期:2008-01-01 00:00:00
abstract::Psilocybin and psilocin are controlled substances in many countries. These are the two main hallucinogenic compounds of the "magic mushrooms" and both act as agonists or partial agonists at 5-hydroxytryptamine (5-HT)2A subtype receptors. During the last few years, psilocybin and psilocin have gained therapeutic releva...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.1080/03602532.2016.1278228
更新日期:2017-02-01 00:00:00
abstract::The aim of this study was to evaluate diazepam and oxazepam as cytochrome P450 inducers at doses previously shown to cause liver tumors in mice but not rats. In rats, diazepam and oxazepam induced CYP2B, and were as effective as phenobarbital despite lacking phenobarbital's tumor-promoting effect in rats. In mice, dia...
journal_title:Drug metabolism reviews
pub_type: 杂志文章
doi:10.1080/03602530600570081
更新日期:2006-01-01 00:00:00
abstract::At present, the methods and enzymology of the UDP-glucuronosyltransferases (UGTs) lag behind that of the cytochromes P450 (CYPs). About 15 human UGTs have been identified, and knowledge about their regulation, substrate selectivity, and tissue distribution has progressed recently. Alamethicin has been characterized as...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.1081/dmr-120000653
更新日期:2001-08-01 00:00:00
abstract::Mineral fibers, including asbestos, are ubiquitous contaminants of the environment. Asbestos fibers are generally present at levels below 1 fiber/L in air though 10 fibers/L may be found in cities; these levels do not appear to be high enough to present a hazard to health. These fibers come mostly from the use of fibr...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.3109/03602539408998321
更新日期:1994-01-01 00:00:00
abstract::An association between marijuana use and schizophrenia has been noted for decades, and the recent emergence of high-efficacy synthetic cannabinoids (SCBs) as drugs of abuse has lead to a growing number of clinical reports of persistent psychotic effects in users of these substances. The mechanisms underlying SCB-elici...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.1080/03602532.2018.1428343
更新日期:2018-02-01 00:00:00
abstract::Ronald Estabrook made his initial impact studying cytochrome P450 by demonstrating the oxidative metabolism function of this unique class of enzymes, which had an unusual spectral peak at 450 nm when reduced and in the presence of carbon monoxide. Utilizing a photochemical action spectrum, he demonstrated that a cytoc...
journal_title:Drug metabolism reviews
pub_type: 传,历史文章,杂志文章
doi:10.1080/03602530701468318
更新日期:2007-01-01 00:00:00
abstract::Traditional Chinese medicine (TCM) has a long history of medical use in China and is still used worldwide. Unexpected herb-drug interactions (HDIs) may lead to adverse drug reactions or loss of therapeutic efficacy of the victim drug. Here, based on searches of Medline, EBSCO, Science Direct and Web of Science using v...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.3109/03602532.2015.1124888
更新日期:2016-01-01 00:00:00
abstract::Glutathione S-transferase P1-1 (GSTP) is one member of the family of GSTs and is ubiquitously expressed in human tissues. The literature is replete with reports of high levels of GSTP linked either with cancer incidence or drug resistance, and yet no entirely cogent explanation for these correlations exists. The catal...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.3109/03602532.2011.552912
更新日期:2011-05-01 00:00:00
abstract::Cytochrome P450-based cancer gene therapy is a novel prodrug activation strategy for cancer treatment that has substantial potential for improving the safety and efficacy of cancer chemotherapeutics. The primary goal of this strategy is to selectively increase tumor cell exposure to cytotoxic drug metabolites generate...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.1081/dmr-100101933
更新日期:1999-05-01 00:00:00
abstract::Hepatotoxicity is a serious problem during drug development and for the use of many established drugs. For example, acetaminophen overdose is currently the most frequent cause of acute liver failure in the United States and Great Britain. Evaluation of the mechanisms of drug-induced liver injury indicates that mitocho...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.3109/03602532.2011.602688
更新日期:2012-02-01 00:00:00
abstract::Xenobiotic metabolism, a ubiquitous natural response to foreign compounds, elicits initiating signals for many pathophysiological events. Currently, most widely used techniques for identifying xenobiotic metabolites and metabolic pathways are empirical and largely based on in vitro incubation assays and in vivo radiot...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.1080/03602530701497804
更新日期:2007-01-01 00:00:00
abstract::1. The metabolic activity of the gastrointestinal microflora can be modified by numerous factors derived from the host, the host's environment, and the flora itself. 2. Marked differences exist in microbial composition and metabolism of the gut floras of different species of animal, and in the degree of colonization o...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.3109/03602538808994135
更新日期:1988-01-01 00:00:00
abstract::Most foreign compounds, including nonnutrients in foods and vapors in air, undergo extensive metabolism before they are eliminated from the body. Included in this paper are discussions of the urinary clearance of various kinds of foreign compounds, the nonspecific enzymes that catalyze the formation of many metabolite...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.3109/03602537908993901
更新日期:1979-01-01 00:00:00
abstract::S-carboxymethyl-L-cysteine, the side-chain carboxymethyl derivative of the sulfur-containing amino acid, cysteine, has been known and available for almost 80 years. During this time, it has been put to a variety of uses, but it is within the field of respiratory medicine that, presently, it has found a clinical niche....
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.3109/03602532.2011.631015
更新日期:2012-05-01 00:00:00
abstract::Cyclindole was extensively metabolized and eliminated primarily via the kidneys from most laboratory animals and man. Only in the dog was cyclindole a major urinary component. Cyclindole was metabolized by N-demethylation and/or hydroxylation. In studies utilizing radiolabeled drug, the primary urinary component was p...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.3109/03602538008994027
更新日期:1980-01-01 00:00:00
abstract::Human tumors arise from multiple genetic changes that gradually transform growth-limited cells into highly invasive cells that are unresponsive to growth controls. The genetic evolution of normal cells into cancer cells is largely determined by the fidelity of DNA replication, repair, and division. Cell-cycle arrest i...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.1081/dmr-100102335
更新日期:2000-08-01 00:00:00
abstract::Gold Nanostars (GNS) have attracted tremendous attention toward themselves owing to their multi-branched structure and unique properties. These state of the art metallic nanoparticles possess intrinsic features like remarkable optical properties and exceptional physiochemical activities. These star-shaped gold nanopar...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.1080/03602532.2020.1734021
更新日期:2020-05-01 00:00:00
abstract::In this paper, we evaluate methodologies and null mouse models used to study drug transporter function in vitro and in vivo. P-glycoprotein and MRP null mice have been used to examine many aspects of xenobiotic distribution and bioavailability. Their advantage over conventional models is that they allow the exclusion ...
journal_title:Drug metabolism reviews
pub_type: 杂志文章,评审
doi:10.1080/03602530802605040
更新日期:2009-01-01 00:00:00