Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.toxlet.2008.06.001
DC FieldValue
dc.titlePrevention of acetaminophen (APAP)-induced hepatotoxicity by leflunomide via inhibition of APAP biotransformation to N-acetyl-p-benzoquinone imine
dc.contributor.authorTan, S.C.
dc.contributor.authorNew, L.S.
dc.contributor.authorChan, E.C.Y.
dc.date.accessioned2014-10-29T01:57:21Z
dc.date.available2014-10-29T01:57:21Z
dc.date.issued2008-08-28
dc.identifier.citationTan, S.C., New, L.S., Chan, E.C.Y. (2008-08-28). Prevention of acetaminophen (APAP)-induced hepatotoxicity by leflunomide via inhibition of APAP biotransformation to N-acetyl-p-benzoquinone imine. Toxicology Letters 180 (3) : 174-181. ScholarBank@NUS Repository. https://doi.org/10.1016/j.toxlet.2008.06.001
dc.identifier.issn03784274
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/106256
dc.description.abstractAcetaminophen (APAP) is safe at therapeutic levels but causes liver injury via N-acetyl-p-benzoquinone imine (NAPQI)-induced oxidative stress when overdose. Recent studies indicated that mitochondrial permeability transition (mPT) plays a key role in APAP-induced toxicity and leflunomide (LEF) protects against the toxicity through inhibition of c-jun NH2-terminal protein kinase (JNK)-mediated pathway of mPT. It is not clearly understood if LEF also exerts its protective effect through inhibition of APAP bioactivation to the toxic NAPQI. The present work was undertaken to study the effect of LEF on the bioactivation of APAP to NAPQI. Mechanism-based inhibition incubations performed in mouse and human liver microsomes (MLM and HLM) indicated that inhibition of APAP bioactivation to NAPQI was observed in MLM but not in HLM. Furthermore, LEF but not its active metabolite, A77-1726, was shown to be the main inhibitor. When APAP and LEF were incubated with human recombinant P450 enzymes, CYP1A2 was found to be the isozyme responsible for the inhibition of APAP bioactivation. Species variation in CYP1A2 enzymes probably accounted for the different observations in our MLM and HLM studies. We concluded that inhibition of NAPQI formation is not a probable pathway that LEF protects APAP-induced hepatotoxicity in human. © 2008 Elsevier Ireland Ltd. All rights reserved.
dc.description.urihttp://libproxy1.nus.edu.sg/login?url=http://dx.doi.org/10.1016/j.toxlet.2008.06.001
dc.sourceScopus
dc.subjectA77-1726
dc.subjectAcetaminophen
dc.subjectHepatotoxicity
dc.subjectLeflunomide
dc.subjectMicrosomes
dc.subjectN-Acetyl-p-benzoquinone imine
dc.typeArticle
dc.contributor.departmentPHARMACY
dc.description.doi10.1016/j.toxlet.2008.06.001
dc.description.sourcetitleToxicology Letters
dc.description.volume180
dc.description.issue3
dc.description.page174-181
dc.description.codenTOLED
dc.identifier.isiut000259461000003
Appears in Collections:Staff Publications

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