Identification of early biomarkers during acetaminophen-induced hepatotoxicity by fourier transform infrared microspectroscopy
Acetaminophen is a widely prescribed drug used to relieve pain and fever; however, it is a leading cause of drug-induced liver injury and a burden on public healthcare. In this study, hepatotoxicity in mice post oral dosing of acetaminophen was investigated using liver and sera samples with Fourier...
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| Veröffentlicht in: | PloS one 2012-09, Vol.7 (9), p.e45521 |
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| description | Acetaminophen is a widely prescribed drug used to relieve pain and fever; however, it is a leading cause of drug-induced liver injury and a burden on public healthcare. In this study, hepatotoxicity in mice post oral dosing of acetaminophen was investigated using liver and sera samples with Fourier Transform Infrared microspectroscopy. The infrared spectra of acetaminophen treated livers in BALB/c mice show decrease in glycogen, increase in amounts of cholesteryl esters and DNA respectively. Rescue experiments using L-methionine demonstrate that depletion in glycogen and increase in DNA are abrogated with pre-treatment, but not post-treatment, with L-methionine. This indicates that changes in glycogen and DNA are more sensitive to the rapid depletion of glutathione. Importantly, analysis of sera identified lowering of glycogen and increase in DNA and chlolesteryl esters earlier than increase in alanine aminotransferase, which is routinely used to diagnose liver damage. In addition, these changes are also observed in C57BL/6 and Nos2(-/-) mice. There is no difference in the kinetics of expression of these three molecules in both strains of mice, the extent of damage is similar and corroborated with ALT and histological analysis. Quantification of cytokines in sera showed increase upon APAP treatment. Although the levels of Tnfα and Ifnγ in sera are not significantly affected, Nos2(-/-) mice display lower Il6 but higher Il10 levels during this acute model of hepatotoxicity. Overall, this study reinforces the growing potential of Fourier Transform Infrared microspectroscopy as a fast, highly sensitive and label-free technique for non-invasive diagnosis of liver damage. The combination of Fourier Transform Infrared microspectroscopy and cytokine analysis is a powerful tool to identify multiple biomarkers, understand differential host responses and evaluate therapeutic regimens during liver damage and, possibly, other diseases. |
| doi_str_mv | 10.1371/journal.pone.0045521 |
| format | Article |
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In this study, hepatotoxicity in mice post oral dosing of acetaminophen was investigated using liver and sera samples with Fourier Transform Infrared microspectroscopy. The infrared spectra of acetaminophen treated livers in BALB/c mice show decrease in glycogen, increase in amounts of cholesteryl esters and DNA respectively. Rescue experiments using L-methionine demonstrate that depletion in glycogen and increase in DNA are abrogated with pre-treatment, but not post-treatment, with L-methionine. This indicates that changes in glycogen and DNA are more sensitive to the rapid depletion of glutathione. Importantly, analysis of sera identified lowering of glycogen and increase in DNA and chlolesteryl esters earlier than increase in alanine aminotransferase, which is routinely used to diagnose liver damage. In addition, these changes are also observed in C57BL/6 and Nos2(-/-) mice. There is no difference in the kinetics of expression of these three molecules in both strains of mice, the extent of damage is similar and corroborated with ALT and histological analysis. Quantification of cytokines in sera showed increase upon APAP treatment. Although the levels of Tnfα and Ifnγ in sera are not significantly affected, Nos2(-/-) mice display lower Il6 but higher Il10 levels during this acute model of hepatotoxicity. Overall, this study reinforces the growing potential of Fourier Transform Infrared microspectroscopy as a fast, highly sensitive and label-free technique for non-invasive diagnosis of liver damage. The combination of Fourier Transform Infrared microspectroscopy and cytokine analysis is a powerful tool to identify multiple biomarkers, understand differential host responses and evaluate therapeutic regimens during liver damage and, possibly, other diseases.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0045521</identifier><identifier>PMID: 23029070</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acetaminophen ; Acetaminophen - administration & dosage ; Acetaminophen - adverse effects ; Alanine ; Alanine transaminase ; Analgesics ; Animals ; Apoptosis ; Biochemistry ; Biological markers ; Biology ; Biomarkers ; Biomarkers - blood ; Biomarkers - metabolism ; Causes of ; Chemical and Drug Induced Liver Injury - blood ; Chemical and Drug Induced Liver Injury - metabolism ; Chemical and Drug Induced Liver Injury - pathology ; Cholesterol Esters - blood ; Cholesterol Esters - metabolism ; Complications and side effects ; Cytochrome ; Cytokines ; Cytokines - blood ; Cytokines - metabolism ; Damage assessment ; Deoxyribonucleic acid ; Depletion ; Diagnosis ; DNA ; DNA - blood ; DNA - metabolism ; Dosage and administration ; Esters ; Fever ; Fourier transforms ; Genetic aspects ; Glutathione ; Glycogen ; Glycogen - blood ; Glycogen - metabolism ; Health care ; Hepatotoxicity ; Infrared analysis ; Infrared spectra ; Infrared spectroscopy ; Interleukin 1 ; Interleukin 10 ; Interleukin 6 ; Kinetics ; Liver ; Liver - drug effects ; Liver - metabolism ; Liver - pathology ; Liver diseases ; Medical imaging ; Medicine ; Metabolism ; Metabolites ; Methionine ; Methionine - adverse effects ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nitric oxide ; Nitric Oxide Synthase Type II - genetics ; Nitric Oxide Synthase Type II - metabolism ; NMR ; Nuclear magnetic resonance ; Pain ; Physical chemistry ; Rodents ; Science ; Spectroscopy, Fourier Transform Infrared ; Tomography ; γ-Interferon</subject><ispartof>PloS one, 2012-09, Vol.7 (9), p.e45521</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>Gautam et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2012 Gautam et al 2012 Gautam et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-ab1301aa1ce9b6bbaadec6a4dedff0dc5c89afff766965d599a0a11adc50ee503</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446881/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446881/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23029070$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Mukhopadhyay, Partha</contributor><creatorcontrib>Gautam, Rekha</creatorcontrib><creatorcontrib>Chandrasekar, Bhagawat</creatorcontrib><creatorcontrib>Deobagkar-Lele, Mukta</creatorcontrib><creatorcontrib>Rakshit, Srabanti</creatorcontrib><creatorcontrib>Kumar B N, Vinay</creatorcontrib><creatorcontrib>Umapathy, Siva</creatorcontrib><creatorcontrib>Nandi, Dipankar</creatorcontrib><title>Identification of early biomarkers during acetaminophen-induced hepatotoxicity by fourier transform infrared microspectroscopy</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Acetaminophen is a widely prescribed drug used to relieve pain and fever; however, it is a leading cause of drug-induced liver injury and a burden on public healthcare. In this study, hepatotoxicity in mice post oral dosing of acetaminophen was investigated using liver and sera samples with Fourier Transform Infrared microspectroscopy. The infrared spectra of acetaminophen treated livers in BALB/c mice show decrease in glycogen, increase in amounts of cholesteryl esters and DNA respectively. Rescue experiments using L-methionine demonstrate that depletion in glycogen and increase in DNA are abrogated with pre-treatment, but not post-treatment, with L-methionine. This indicates that changes in glycogen and DNA are more sensitive to the rapid depletion of glutathione. Importantly, analysis of sera identified lowering of glycogen and increase in DNA and chlolesteryl esters earlier than increase in alanine aminotransferase, which is routinely used to diagnose liver damage. In addition, these changes are also observed in C57BL/6 and Nos2(-/-) mice. There is no difference in the kinetics of expression of these three molecules in both strains of mice, the extent of damage is similar and corroborated with ALT and histological analysis. Quantification of cytokines in sera showed increase upon APAP treatment. Although the levels of Tnfα and Ifnγ in sera are not significantly affected, Nos2(-/-) mice display lower Il6 but higher Il10 levels during this acute model of hepatotoxicity. Overall, this study reinforces the growing potential of Fourier Transform Infrared microspectroscopy as a fast, highly sensitive and label-free technique for non-invasive diagnosis of liver damage. The combination of Fourier Transform Infrared microspectroscopy and cytokine analysis is a powerful tool to identify multiple biomarkers, understand differential host responses and evaluate therapeutic regimens during liver damage and, possibly, other diseases.</description><subject>Acetaminophen</subject><subject>Acetaminophen - administration & dosage</subject><subject>Acetaminophen - adverse effects</subject><subject>Alanine</subject><subject>Alanine transaminase</subject><subject>Analgesics</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biochemistry</subject><subject>Biological markers</subject><subject>Biology</subject><subject>Biomarkers</subject><subject>Biomarkers - blood</subject><subject>Biomarkers - metabolism</subject><subject>Causes of</subject><subject>Chemical and Drug Induced Liver Injury - blood</subject><subject>Chemical and Drug Induced Liver Injury - metabolism</subject><subject>Chemical and Drug Induced Liver Injury - pathology</subject><subject>Cholesterol Esters - blood</subject><subject>Cholesterol Esters - metabolism</subject><subject>Complications and side effects</subject><subject>Cytochrome</subject><subject>Cytokines</subject><subject>Cytokines - blood</subject><subject>Cytokines - metabolism</subject><subject>Damage assessment</subject><subject>Deoxyribonucleic acid</subject><subject>Depletion</subject><subject>Diagnosis</subject><subject>DNA</subject><subject>DNA - blood</subject><subject>DNA - metabolism</subject><subject>Dosage and administration</subject><subject>Esters</subject><subject>Fever</subject><subject>Fourier transforms</subject><subject>Genetic aspects</subject><subject>Glutathione</subject><subject>Glycogen</subject><subject>Glycogen - blood</subject><subject>Glycogen - metabolism</subject><subject>Health care</subject><subject>Hepatotoxicity</subject><subject>Infrared analysis</subject><subject>Infrared spectra</subject><subject>Infrared spectroscopy</subject><subject>Interleukin 1</subject><subject>Interleukin 10</subject><subject>Interleukin 6</subject><subject>Kinetics</subject><subject>Liver</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Liver diseases</subject><subject>Medical imaging</subject><subject>Medicine</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Methionine</subject><subject>Methionine - adverse effects</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Nitric oxide</subject><subject>Nitric Oxide Synthase Type II - genetics</subject><subject>Nitric Oxide Synthase Type II - metabolism</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Pain</subject><subject>Physical chemistry</subject><subject>Rodents</subject><subject>Science</subject><subject>Spectroscopy, Fourier Transform Infrared</subject><subject>Tomography</subject><subject>γ-Interferon</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl2L1DAYhYso7rr6D0QLguDFjEnbZNIbYVn8GFhY8Os2vE3ezGRtm26Sys6Nv92M012moCC9SEme9-T09GTZc0qWtFzRt9du9D20y8H1uCSkYqygD7JTWpfFghekfHj0fpI9CeGaEFYKzh9nJ0VJipqsyGn2a62xj9ZYBdG6PncmR_DtLm-s68D_QB9yPXrbb3JQGKGzvRu22C9sr0eFOt_iANFFd2uVjWlsl5tkzKLPo4c-GOe73PbGg09wZ5V3YUAV06LcsHuaPTLQBnw2rWfZtw_vv158WlxefVxfnF8uFK-LuICGloQCUIV1w5sGQKPiUGnUxhCtmBI1GGNWnNecaVbXQIBSSCcEkZHyLHt50B1aF-QUXZC0rCq24lVVJGJ9ILSDazl4m75-Jx1Y-WfD-Y0EH61qUVaCG7aiukBSVaXmglGjiYCaCFETxpLWu-m2selQq5Swh3YmOj_p7VZu3E-Z7HAhaBJ4NQl4dzNiiP-wPFEbSK5SyC6Jqc4GJc-rWhS8oGJvZvkXKj0a0-9I5TE27c8G3swGEhPxNm5gDEGuv3z-f_bq-5x9fcRuEdq4Da4d970Lc7A6gPuyBI_mPjlK5L77d2nIfffl1P009uI49fuhu7KXvwE3cwPg</recordid><startdate>20120919</startdate><enddate>20120919</enddate><creator>Gautam, Rekha</creator><creator>Chandrasekar, Bhagawat</creator><creator>Deobagkar-Lele, Mukta</creator><creator>Rakshit, Srabanti</creator><creator>Kumar B N, Vinay</creator><creator>Umapathy, Siva</creator><creator>Nandi, Dipankar</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120919</creationdate><title>Identification of early biomarkers during acetaminophen-induced hepatotoxicity by fourier transform infrared microspectroscopy</title><author>Gautam, Rekha ; Chandrasekar, Bhagawat ; Deobagkar-Lele, Mukta ; Rakshit, Srabanti ; Kumar B N, Vinay ; Umapathy, Siva ; Nandi, Dipankar</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-ab1301aa1ce9b6bbaadec6a4dedff0dc5c89afff766965d599a0a11adc50ee503</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Acetaminophen</topic><topic>Acetaminophen - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gautam, Rekha</au><au>Chandrasekar, Bhagawat</au><au>Deobagkar-Lele, Mukta</au><au>Rakshit, Srabanti</au><au>Kumar B N, Vinay</au><au>Umapathy, Siva</au><au>Nandi, Dipankar</au><au>Mukhopadhyay, Partha</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of early biomarkers during acetaminophen-induced hepatotoxicity by fourier transform infrared microspectroscopy</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-09-19</date><risdate>2012</risdate><volume>7</volume><issue>9</issue><spage>e45521</spage><pages>e45521-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Acetaminophen is a widely prescribed drug used to relieve pain and fever; however, it is a leading cause of drug-induced liver injury and a burden on public healthcare. In this study, hepatotoxicity in mice post oral dosing of acetaminophen was investigated using liver and sera samples with Fourier Transform Infrared microspectroscopy. The infrared spectra of acetaminophen treated livers in BALB/c mice show decrease in glycogen, increase in amounts of cholesteryl esters and DNA respectively. Rescue experiments using L-methionine demonstrate that depletion in glycogen and increase in DNA are abrogated with pre-treatment, but not post-treatment, with L-methionine. This indicates that changes in glycogen and DNA are more sensitive to the rapid depletion of glutathione. Importantly, analysis of sera identified lowering of glycogen and increase in DNA and chlolesteryl esters earlier than increase in alanine aminotransferase, which is routinely used to diagnose liver damage. In addition, these changes are also observed in C57BL/6 and Nos2(-/-) mice. There is no difference in the kinetics of expression of these three molecules in both strains of mice, the extent of damage is similar and corroborated with ALT and histological analysis. Quantification of cytokines in sera showed increase upon APAP treatment. Although the levels of Tnfα and Ifnγ in sera are not significantly affected, Nos2(-/-) mice display lower Il6 but higher Il10 levels during this acute model of hepatotoxicity. Overall, this study reinforces the growing potential of Fourier Transform Infrared microspectroscopy as a fast, highly sensitive and label-free technique for non-invasive diagnosis of liver damage. The combination of Fourier Transform Infrared microspectroscopy and cytokine analysis is a powerful tool to identify multiple biomarkers, understand differential host responses and evaluate therapeutic regimens during liver damage and, possibly, other diseases.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23029070</pmid><doi>10.1371/journal.pone.0045521</doi><tpages>e45521</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-09, Vol.7 (9), p.e45521 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1344576442 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Acetaminophen Acetaminophen - administration & dosage Acetaminophen - adverse effects Alanine Alanine transaminase Analgesics Animals Apoptosis Biochemistry Biological markers Biology Biomarkers Biomarkers - blood Biomarkers - metabolism Causes of Chemical and Drug Induced Liver Injury - blood Chemical and Drug Induced Liver Injury - metabolism Chemical and Drug Induced Liver Injury - pathology Cholesterol Esters - blood Cholesterol Esters - metabolism Complications and side effects Cytochrome Cytokines Cytokines - blood Cytokines - metabolism Damage assessment Deoxyribonucleic acid Depletion Diagnosis DNA DNA - blood DNA - metabolism Dosage and administration Esters Fever Fourier transforms Genetic aspects Glutathione Glycogen Glycogen - blood Glycogen - metabolism Health care Hepatotoxicity Infrared analysis Infrared spectra Infrared spectroscopy Interleukin 1 Interleukin 10 Interleukin 6 Kinetics Liver Liver - drug effects Liver - metabolism Liver - pathology Liver diseases Medical imaging Medicine Metabolism Metabolites Methionine Methionine - adverse effects Mice Mice, Inbred C57BL Mice, Knockout Nitric oxide Nitric Oxide Synthase Type II - genetics Nitric Oxide Synthase Type II - metabolism NMR Nuclear magnetic resonance Pain Physical chemistry Rodents Science Spectroscopy, Fourier Transform Infrared Tomography γ-Interferon |
| title | Identification of early biomarkers during acetaminophen-induced hepatotoxicity by fourier transform infrared microspectroscopy |
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