Linked Life Data

10775460

Source:http://linkedlifedata.com/resource/pubmed/id/10775460

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2000-6-5
pubmed:abstractText
The hepatic cytosolic hemoprotein tryptophan 2,3-dioxygenase (TDO) is the rate-limiting enzyme in tryptophan catabolism and thus plays a key role in regulating the physiological flux of tryptophan into relevant metabolic pathways. The TDO protein is induced by corticosteroids such as dexamethasone (DEX) and is stabilized by its prosthetic heme. In rats, acute chemically induced hepatic heme depletion reduces the functional hepatic TDO levels to 25-30% of basal levels within 1 h, and this decrease persists beyond 28 h of heme depletion at which time only 25-30% of the protein is available for heme incorporation. Since this could stem from impaired de novo synthesis and/or instability of the newly synthesized apoTDO protein in the absence of heme, we examined the specific role of heme in these events in a previously validated rat model of acute hepatic heme depletion triggered by the P450 suicide substrate 3, 5-dicarbethoxy 2,6-dimethyl-4-ethyl-1,4-dihydropyridine. We now show that exogenous heme can reverse the functional impairment of the enzyme observed during hepatic heme depletion and fully restore the impaired DEX-mediated induction of the enzyme to normal. Furthermore, through Northern/slot blot analyses coupled with nuclear run-on studies, we now document that this heme regulation of TDO is exerted primarily at the transcriptional level. Immunoblotting analyses also reveal corresponding changes in the TDO protein, thereby establishing that heme is necessary for DEX-inducible TDO mRNA transcription and subsequent translation. Thus, the TDO gene may contain heme-regulatory elements in addition to the reported glucocorticoid-responsive elements. Together, these findings suggest that clinically, hepatic heme deficiency may enhance the tryptophan flux into synthetic (serotonergic) pathways, not only by depriving prosthetic heme for a functionally competent TDO hemoprotein, its primary catabolic enzyme, but also by impairing the de novo synthesis of this enzyme.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0003-9861
pubmed:author
pubmed:copyrightInfo
Copyright 2000 Academic Press.
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
377
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
195-203
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:10775460-Animals, pubmed-meshheading:10775460-Blotting, Western, pubmed-meshheading:10775460-Cytochrome P-450 Enzyme System, pubmed-meshheading:10775460-Dexamethasone, pubmed-meshheading:10775460-Dicarbethoxydihydrocollidine, pubmed-meshheading:10775460-Dose-Response Relationship, Drug, pubmed-meshheading:10775460-Enzyme Induction, pubmed-meshheading:10775460-Gene Expression Regulation, Enzymologic, pubmed-meshheading:10775460-Heme, pubmed-meshheading:10775460-Hemin, pubmed-meshheading:10775460-Holoenzymes, pubmed-meshheading:10775460-Liver, pubmed-meshheading:10775460-Male, pubmed-meshheading:10775460-RNA, Messenger, pubmed-meshheading:10775460-Rats, pubmed-meshheading:10775460-Rats, Sprague-Dawley, pubmed-meshheading:10775460-Transcription, Genetic, pubmed-meshheading:10775460-Tryptophan Oxygenase
pubmed:year
2000
pubmed:articleTitle
Heme: a regulator of rat hepatic tryptophan 2,3-dioxygenase?
pubmed:affiliation
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94143, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.