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Article: Hemin administration to rats reduces levels of hepatic mRNAs for phenobarbitone-inducible enzymes

TitleHemin administration to rats reduces levels of hepatic mRNAs for phenobarbitone-inducible enzymes
Authors
Issue Date1990
PublisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.org
Citation
Molecular Pharmacology, 1990, v. 38 n. 4, p. 486-493 How to Cite?
AbstractThe levels of hepatic mRNAs for several enzymes involved in drug metabolism were measured following administration to rats of either phenobarbitone or 2-allyl-2-isopropylacetamide. There was a substantial elevation in the mRNA levels for cytochromes P450 IIB1, IIB2, and IIIA1, epoxide hydrolase, glutathione-S-transferase Y(a)/Y(c) subunit, UDP-glucuronosyltransferase isoenzyme (UDPGT(r)-2), NADPH-cytochrome P450 oxidoreductase, and 5-aminolevulinate synthase. When rats were treated with hemin, together with inducing drug, there was a marked reduction in the induced levels of these mRNAs, with decreases in the range of 55-95%. Basal levels of these mRNAs in the noninduced rat liver were also lowered by hemin administration. Nuclear run-on transcriptional experiments showed that hemin administration substantially lowered both the basal and drug-induced transcriptional activities of the genes for cytochrome P450IIB1/IIB2 and 5-aminolevulinate synthase. In contrast, the mRNA for heme oxygenase was elevated by hemin treatment, whereas the mRNA levels of β-actin, albumin, and ornithine transcarbamylase, used as controls, were not affected. Treatment of rats with clofibrate resulted in increased levels of mRNA for cytochrome IVA1 and, in additon, those for cytochromes P450IIB1 and P450IIB2. Hemin administration repressed the induction of mRNA levels for cytochromes P450IIB1 and IIb2 but not that for cytochrome P450IVA1. Additionally, the induction of P450IAI by β-naphthoflavone was not affected by hemin. The results suggest that heme may negatively control the induction of cytochromes P450IIB1 and IIB2 and other hepatic enzymes by phenobarbitone and phenobarbitone-like drugs and perhaps play a role in regulating drug metabolism. There is, however, no evidence at present as to whether heme has a direct role in such a mechanism or whether injected hemin promotes a secondary response.
Persistent Identifierhttp://hdl.handle.net/10722/147849
ISSN
2015 Impact Factor: 3.931
2015 SCImago Journal Rankings: 2.047
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorSrivastava, Gen_US
dc.contributor.authorHansen, AJen_US
dc.contributor.authorBawden, MJen_US
dc.contributor.authorMay, BKen_US
dc.date.accessioned2012-05-29T06:09:33Z-
dc.date.available2012-05-29T06:09:33Z-
dc.date.issued1990en_US
dc.identifier.citationMolecular Pharmacology, 1990, v. 38 n. 4, p. 486-493en_US
dc.identifier.issn0026-895Xen_US
dc.identifier.urihttp://hdl.handle.net/10722/147849-
dc.description.abstractThe levels of hepatic mRNAs for several enzymes involved in drug metabolism were measured following administration to rats of either phenobarbitone or 2-allyl-2-isopropylacetamide. There was a substantial elevation in the mRNA levels for cytochromes P450 IIB1, IIB2, and IIIA1, epoxide hydrolase, glutathione-S-transferase Y(a)/Y(c) subunit, UDP-glucuronosyltransferase isoenzyme (UDPGT(r)-2), NADPH-cytochrome P450 oxidoreductase, and 5-aminolevulinate synthase. When rats were treated with hemin, together with inducing drug, there was a marked reduction in the induced levels of these mRNAs, with decreases in the range of 55-95%. Basal levels of these mRNAs in the noninduced rat liver were also lowered by hemin administration. Nuclear run-on transcriptional experiments showed that hemin administration substantially lowered both the basal and drug-induced transcriptional activities of the genes for cytochrome P450IIB1/IIB2 and 5-aminolevulinate synthase. In contrast, the mRNA for heme oxygenase was elevated by hemin treatment, whereas the mRNA levels of β-actin, albumin, and ornithine transcarbamylase, used as controls, were not affected. Treatment of rats with clofibrate resulted in increased levels of mRNA for cytochrome IVA1 and, in additon, those for cytochromes P450IIB1 and P450IIB2. Hemin administration repressed the induction of mRNA levels for cytochromes P450IIB1 and IIb2 but not that for cytochrome P450IVA1. Additionally, the induction of P450IAI by β-naphthoflavone was not affected by hemin. The results suggest that heme may negatively control the induction of cytochromes P450IIB1 and IIB2 and other hepatic enzymes by phenobarbitone and phenobarbitone-like drugs and perhaps play a role in regulating drug metabolism. There is, however, no evidence at present as to whether heme has a direct role in such a mechanism or whether injected hemin promotes a secondary response.en_US
dc.languageengen_US
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.orgen_US
dc.relation.ispartofMolecular Pharmacologyen_US
dc.subject.mesh5-Aminolevulinate Synthetase - Geneticsen_US
dc.subject.meshAnimalsen_US
dc.subject.meshCytochrome P-450 Enzyme System - Geneticsen_US
dc.subject.meshEnzyme Induction - Drug Effectsen_US
dc.subject.meshHemin - Pharmacologyen_US
dc.subject.meshLiver - Enzymologyen_US
dc.subject.meshMaleen_US
dc.subject.meshPhenobarbital - Pharmacologyen_US
dc.subject.meshRna, Messenger - Analysisen_US
dc.subject.meshRatsen_US
dc.subject.meshRats, Inbred Strainsen_US
dc.subject.meshTranscription, Genetic - Drug Effectsen_US
dc.titleHemin administration to rats reduces levels of hepatic mRNAs for phenobarbitone-inducible enzymesen_US
dc.typeArticleen_US
dc.identifier.emailSrivastava, G:gopesh@pathology.hku.hken_US
dc.identifier.authoritySrivastava, G=rp00365en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.pmid2233690-
dc.identifier.scopuseid_2-s2.0-0025006183en_US
dc.identifier.volume38en_US
dc.identifier.issue4en_US
dc.identifier.spage486en_US
dc.identifier.epage493en_US
dc.identifier.isiWOS:A1990ED70400009-
dc.publisher.placeUnited Statesen_US

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