Journal of drug metabolism & toxicology最新文献

{"title":"Comparative Metabolism of Batracylin (NSC 320846) and N-acetylbatracylin (NSC 611001) Using Human, Dog, and Rat Preparations <i>In Vitro</i>.","authors":"Joseph M Covey,&nbsp;Joel M Reid,&nbsp;Sarah A Buhrow,&nbsp;Mary Kuffel,&nbsp;Chad Walden,&nbsp;Holger Behrsing,&nbsp;Matthew M Ames","doi":"10.4172/2157-7609.1000203","DOIUrl":"https://doi.org/10.4172/2157-7609.1000203","url":null,"abstract":"<p><strong>Background: </strong>Batracylin is a heterocyclic arylamine topoisomerase inhibitor with preclinical anticancer activity. Marked species differences in sensitivity to the toxicity of batracylin were observed and attributed to differential formation of N-acetylbatracylin by N-acetyltransferase. A Phase I trial of batracylin in cancer patients with slow acetylator genotypes identified a dose-limiting toxicity of hemorrhagic cystitis. To further explore the metabolism of batracylin and N-acetylbatracylin across species, detailed studies using human, rat, and dog liver microsomal and hepatocyte preparations were conducted.</p><p><strong>Methods: </strong>Batracylin or N-acetylbatracylin was incubated with microsomes and hepatocytes from human, rat, and dog liver and with CYP-expressing human and rat microsomes. Substrates and metabolites were analyzed by HPLC with diode array, fluorescence, radiochemical, or mass spectrometric detection. Covalent binding of radiolabeled batracylin and N-acetylbatracylin to protein and DNA was measured in 3-methylcholanthrene-induced rat, human, and dog liver microsomes, and with recombinant human cytochromes P450.</p><p><strong>Results: </strong>In microsomal preparations, loss of batracylin was accompanied by formation of one hydroxylated metabolite in human liver microsomes and five hydroxylated metabolites in rat liver microsomes. Six mono- or di-hydroxy-N-acetylbatracylin metabolites were found in incubations of this compound with 3MC rat liver microsomes. Hydroxylation sites were identified for some of the metabolites using deuterated substrates. Incubation with recombinant cytochromes P450 identified rCYP1A1, rCYP1A2, hCYP1A1 and hCYP1B1 as the major CYP isoforms that metabolize batracylin and N-acetylbatracylin. Glucuronide conjugates of batracylin were also identified in hepatocyte incubations. NADPH-dependent covalent binding to protein and DNA was detected in all batracylin and most N-acetylbatracylin preparations evaluated.</p><p><strong>Conclusions: </strong>Microsomal metabolism of batracylin and N-acetylbatracylin results in multiple hydroxylated products (including possible hydroxylamines) and glutathione conjugates. Incubation of batracylin with hepatocytes resulted in production primarily of glucuronides and other conjugates. There was no clear distinction in the metabolism of batracylin and N-acetylbatracylin across species that would explain the differential toxicity.</p>","PeriodicalId":89412,"journal":{"name":"Journal of drug metabolism & toxicology","volume":"7 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4172/2157-7609.1000203","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34689586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IS METABOLIC ACTIVATION OF TOPOISOMERASE II POISONS IMPORTANT IN THE MECHANISM OF CYTOTOXICITY?","authors":"Birandra K Sinha,&nbsp;Ronald P Mason","doi":"10.4172/2157-7609.1000186","DOIUrl":"https://doi.org/10.4172/2157-7609.1000186","url":null,"abstract":"<p><p>The antitumor drugs doxorubicin and etoposide, a phodophyllotoxin derivative, are clinically active for the treatment of human malignancies. Because of their extreme effectiveness in the clinic, their modes of actions have been the subject of intense research for over several decades both in the laboratory and in the clinic. It has been found that both doxorubicin and etoposide (VP-16) act on topoisomerase II, induce DNA cleavage, and form double-strand breaks, causing tumor cell death. However, both of these drugs also undergo extensive metabolism in tumor cells and <i>in vivo</i> to various reactive intermediates that bind covalently to cellular DNA and proteins. Moreover, both drugs are metabolized to reactive free radicals that induce lipid peroxidation and DNA damage. However, the role of drug activation in the mechanism of cytotoxicity remains poorly defined. In this review, we critically evaluate the significance of metabolic activation of doxorubicin and etoposide in the mechanism of tumor cytotoxicity.</p>","PeriodicalId":89412,"journal":{"name":"Journal of drug metabolism & toxicology","volume":"6 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4172/2157-7609.1000186","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37307122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ubiquitin-Proteasome System in Neurodegenerative Disorders.","authors":"Geeta Rao, Brandon Croft, Chengwen Teng, Vibhudutta Awasthi","doi":"10.4172/2157-7609.1000187","DOIUrl":"10.4172/2157-7609.1000187","url":null,"abstract":"<p><p>Cellular proteostasis is a highly dynamic process and is primarily carried out by the degradation tools of ubiquitin-proteasome system (UPS). Abnormalities in UPS function result in the accumulation of damaged or misfolded proteins which can form intra- and extracellular aggregated proteinaceous deposits leading to cellular dysfunction and/or death. Deposition of abnormal protein aggregates and the cellular inability to clear them have been implicated in the pathogenesis of a number of neurodegenerative disorders such as Alzheimer's and Parkinson's. Contrary to the upregulation of proteasome function in oncogenesis and the use of proteasome inhibition as a therapeutic strategy, activation of proteasome function would serve therapeutic objectives of treatment of neurodegenerative diseases. This review describes the current understanding of the role of the proteasome in neurodegenerative disorders and potential utility of proteasomal modulation therein.</p>","PeriodicalId":89412,"journal":{"name":"Journal of drug metabolism & toxicology","volume":"6 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/2d/28/nihms-1009448.PMC6370320.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36557324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BIOTRANSFORMATION OF HYDRAZINE DERVATIVES IN THE MECHANISM OF TOXICITY.","authors":"Birandra K Sinha,&nbsp;Ronald P Mason","doi":"10.4172/2157-7609.1000168","DOIUrl":"https://doi.org/10.4172/2157-7609.1000168","url":null,"abstract":"<p><p>Hydrazine derivatives are environmental and food pollutants but are also important because of their use in medicine for the treatment of tuberculosis and cancer. However, hydrazines also pose significant health risks to humans as they are mutagenic and carcinogenic. This review examines various metabolic pathways (enzymatic and non-enzymatic) of hydrazines for the formation of reactive species that bind to cellular macromolecules and lead to cellular dysfunction. It is believed that this biotransformation is responsible for the pharmacology and pathophysiology of hydrazine derivatives.</p>","PeriodicalId":89412,"journal":{"name":"Journal of drug metabolism & toxicology","volume":"5 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4172/2157-7609.1000168","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37307121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperglycemia as a Risk Factor of Ischemic Stroke.","authors":"Ziyan Zhang,&nbsp;Jingqi Yan,&nbsp;Honglian Shi","doi":"10.4172/2157-7609.1000153","DOIUrl":"https://doi.org/10.4172/2157-7609.1000153","url":null,"abstract":"<p><p>Diabetes is considered a major risk factor for stroke and is associated with worsened stroke outcomes. Here, we discuss and summarize the mechanisms that have been associated with the increased risk of stroke due to the hyperglycemia in diabetes mellitus. In diabetic stroke models, hyperglycemia exaggerates the following damaging processes: acidosis, accumulation of reactive oxygen species/reactive nitrogen, inflammation and mitochondrial dysfunction. Understanding the mechanism of diabetes acting as a stroke risk factor will definitely assist to reveal issues related to drug metabolism and toxicity in diabetic stroke. In addition, it is suggested that future studies may focus on the mechanisms mediating blood-brain barrier and astrocytes dysfunction under hyperglycemic stroke.</p>","PeriodicalId":89412,"journal":{"name":"Journal of drug metabolism & toxicology","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2013-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32759069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of UDP-glucuronosyltransferase (UGT1A1) Promoter Polymorphisms and Gene Expression on Ethnicity, Stage of Disease, and Menopausal Status in Breast Cancer.","authors":"Athena Starlard-Davenport,&nbsp;Beverly R Word,&nbsp;Beverly Lyn-Cook","doi":"10.4172/2157-7609.S4-001","DOIUrl":"https://doi.org/10.4172/2157-7609.S4-001","url":null,"abstract":"<p><p>Estrogen metabolism, catalyzed by UGTs, is a major drug-metabolic pathway that results in inactivation of estrogens and their metabolites. Alterations in UGTs involved in estrogen metabolism, has been suggested to play a role in breast cancer risk. The purpose of this study was to: 1) compare the mRNA expression levels of UGTs involved in estrogen metabolism in human breast tissues from women; 2) compare UGT1A1 mRNA expression to tumor stage, ethnicity, and menopausal status in a group of human breast tumors and normal breast tissues, and 3) investigate the association between variations in the number of TA repeats in the promoter region of UGT1A1 to gene expression. Quantification of UGT mRNA in breast tissues revealed that UGT1A4, UGT1A10, and UGT2B7 mRNA levels were decreased in breast cancers as compared to normal breast tissues. UGT1A1 mRNA levels were also significantly decreased in breast cancers as compared to normal breast tissues (Tumor: 0.5 ± 0.2; Normal: 4.1 ± 1.3, <i>p</i> = 0.0006). UGT1A1 mRNA down-regulation was strongly correlated with postmenopausal status in breast cancer versus controls (<i>p</i> = 0.04). In all the UGT1A1 genotypes observed in our study, the mean mRNA levels was significantly decreased among breast cancer cases as compared to controls for <i>UGT1A1*1/*1</i> (<i>p</i> = 0.004), <i>UGT1A1*28/*28</i> (<i>p</i> = 0.03) and <i>UGT1A1*28/*37</i> (<i>p</i> = 0.06). Our findings demonstrate that further investigations are necessary to determine the role of UGT1A1 in breast carcinogenesis.</p>","PeriodicalId":89412,"journal":{"name":"Journal of drug metabolism & toxicology","volume":"2012 Suppl 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36609182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex Differences in the Expression of Drug-Metabolizing and Transporter Genes in Human Liver.","authors":"Lun Yang,&nbsp;Yan Li,&nbsp;Huixiao Hong,&nbsp;Ching-Wei Chang,&nbsp;Li-Wu Guo,&nbsp;Beverly Lyn-Cook,&nbsp;Leming Shi,&nbsp;Baitang Ning","doi":"10.4172/2157-7609.1000119","DOIUrl":"https://doi.org/10.4172/2157-7609.1000119","url":null,"abstract":"<p><p>Human sex differences in the gene expression of drug metabolizing enzymes and transporters (DMETs) introduce differences in drug absorption, distribution, metabolism and excretion, possibly affecting drug efficacy and adverse reactions. However, existing studies aimed at identifying dimorphic expression differences of DMET genes are limited by sample size and the number of genes profiled. Focusing on a list of 374 DMET genes, we analyzed a previously published gene expression data set consisting of human male (n=234) and female (n=193) liver samples, and identified 77 genes showing differential expression due to sex. To delineate the biological functionalities and regulatory mechanisms for the differentially expressed DMET genes, we conducted a co-expression network analysis. Moreover, clinical implications of sex differences in the expression of human hepatic DMETs are discussed. This study may contribute to the realization of personalized medicine by better understanding the inter-individual differences between males and females in drug/xenobiotic responses and human disease susceptibilities.</p>","PeriodicalId":89412,"journal":{"name":"Journal of drug metabolism & toxicology","volume":"3 3","pages":"1000119"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35640968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of Cytochrome P450 Conserved Sequence Motifs between Helices E and H: Prediction of Critical Motifs and Residues in Enzyme Functions.","authors":"Numan Oezguen,&nbsp;Santosh Kumar","doi":"10.4172/2157-7609.1000110","DOIUrl":"https://doi.org/10.4172/2157-7609.1000110","url":null,"abstract":"<p><p>Rational approaches have been extensively used to investigate the role of active site residues in cytochrome P450 (CYP) functions. However, recent studies using random mutagenesis suggest an important role for non-active site residues in CYP functions. Meta-analysis of the random mutants showed that 75% of the functionally important non-active site residues are present in 20% of the entire protein between helices E and H (E-H) and conserved sequence motif (CSM) between 7 and 11. The CSM approach was developed recently to investigate the functional role of non-active site residues in CYP2B4. Furthermore, we identified and analyzed the CSM in multiple CYP families and subfamilies in the E-H region. Results from CSM analysis showed that CSM 7, 8, 10, and 11 are conserved in CYP1, CYP2, and CYP3 families, while CSM 9 is conserved only in CYP2 family. Analysis of different CYP2 subfamilies showed that CYP2B and CYP2C have similar characteristics in the CSM, while the characteristics of CYP2A and CYP2D subfamilies are different. Finally, we analyzed CSM 7, 8, 10, and 11, which are common in all the CYP families/subfamilies analyzed, in fifteen important drug-metabolizing CYPs. The results showed that while CSM 8 is most conserved among these CYPs, CSM 7, 9, and 10 have significant variations. We suggest that CSM8 has a common role in all the CYPs that have been analyzed, while CSM 7, 10, and 11 may have relatively specific role within the subfamily. We further suggest that these CSM play important role in opening and closing of the substrate access/egress channel by modulating the flexible/plastic region of the protein. Thus, site-directed mutagenesis of these CSM can be used to study structure-function and dynamic/plasticity-function relationships and to design CYP biocatalysts.</p>","PeriodicalId":89412,"journal":{"name":"Journal of drug metabolism & toxicology","volume":"2 ","pages":"1000110"},"PeriodicalIF":0.0,"publicationDate":"2011-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32839075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gemcitabine Cytotoxicity: Interaction of Efflux and Deamination.","authors":"Dan Rudin,&nbsp;Liang Li,&nbsp;Nifang Niu,&nbsp;Krishna R Kalari,&nbsp;Judith A Gilbert,&nbsp;Matthew M Ames,&nbsp;Liewei Wang","doi":"10.4172/2157-7609.1000107","DOIUrl":"https://doi.org/10.4172/2157-7609.1000107","url":null,"abstract":"<p><p>Gemcitabine is a cytidine analogue used in the treatment of various solid tumors. Little is known about how gemcitabine and its metabolites are transported out of cells. We set out to study the efflux of gemcitabine and the possible consequences of that process in cancer cells. We observed the efflux of gemcitabine and its deaminated metabolite, 2',2'-difluorodeoxyuridine (dFdU) using high performance liquid chromatography and tandem mass spectrometry (LC-MS/MS) after gemcitabine treatment. Non-selective ABCC-transport inhibition with probenecid significantly increased intracellular dFdU concentrations, with a similar trend observed with verapamil, a non-selective ABCB1 and ABCG2 transport inhibitor. Neither probenecid nor verapamil altered intracellular gemcitabine levels after the inhibition of deamination with tetrahydrourudine, suggesting that efflux of dFdU, but not gemcitabine, was mediated by ABC transporters. MTS assays showed that probenecid increased sensitivity to gemcitabine. While dFdU displayed little cytotoxicity, intracellular dFdU accumulation inhibited cytidine deaminase, resulting in increased gemcitabine levels and enhanced cytotoxicity. Knockdown of ABCC3, ABCC5 or ABCC10 individually did not significantly increase gemcitabine sensitivity, suggesting the involvement of multiple transporters. In summary, ABCC-mediated efflux may contribute to gemcitabine resistance through increased dFdU efflux that allows for the continuation of gemcitabine deamination. Reversing efflux-mediated gemcitabine resistance may require broad-based efflux inhibition.</p>","PeriodicalId":89412,"journal":{"name":"Journal of drug metabolism & toxicology","volume":"2 107","pages":"1-10"},"PeriodicalIF":0.0,"publicationDate":"2011-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3144579/pdf/nihms298586.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30045250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}