RGD Reference Report - Characterization of 4-hydroxy-2-nonenal metabolism in stellate cell lines derived from normal and cirrhotic rat liver. - Rat Genome Database

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Characterization of 4-hydroxy-2-nonenal metabolism in stellate cell lines derived from normal and cirrhotic rat liver.

Authors: Reichard, JF  Vasiliou, V  Petersen, DR 
Citation: Reichard JF, etal., Biochim Biophys Acta. 2000 Sep 27;1487(2-3):222-32.
RGD ID: 1641942
Pubmed: PMID:11018474   (View Abstract at PubMed)

During oxidative stress, reactive aldehydes, including trans-4-hydroxy-2-nonenal (4-HNE), are generated by peroxidation of membrane lipids and purportedly stimulate hepatic stellate cells to produce excessive extracellular matrix, including type I collagen. An important question concerning the ability of 4-HNE to modulate collagen production by stellate cells is the potential of these specialized cells to detoxify 4-HNE. The objective of the present study was to characterize the ability of stellate cell lines, derived from normal (NFSC) and cirrhotic (CFSC) rat livers, to metabolize 4-HNE by oxidative, reductive and conjugative pathways. These two stellate cell lines were noted to have differing susceptibilities to the cytotoxic effect of 4-HNE. Treatment of both stellate cell lines with a range of 4-HNE doses demonstrated that the concentration which was cytotoxic to 50% of CFSC (TD(50)) was 25% greater than that for NFSC (967.57+/-9.26 nmol/10(6) cells vs. 769.90+/-5.32 nmol/10(6) cells respectively). The capacity of these cell lines to metabolizes 4-HNE was determined by incubating them in suspension with 50 microM 4-HNE (10 nmol/10(6) cell); 4-HNE elimination and metabolite formation were quantified over a 20 min time course. Both stellate cell lines rapidly metabolized 4-HNE, with the CFSC line eliminating 4-HNE at a rate that was approx. 2-fold greater than the NFSC line. The rate of 4-HNE metabolism attributable to glutathione S-transferase (GST) was similar in both cell lines, though differential cell specific expressions of GST isoforms GSTP1-1 and GSTA4-4 were observed. The greater rate of 4-HNE elimination by CFSC was attributable to its aldehyde dehydrogenase (ALDH) activity which accounted for approx. 50% of 4-HNE metabolism in CFSC but was insignificant in NFSC. Neither cell line had detectable alcohol dehydrogenase activity or protein levels. Measurement of cellular GSH concentrations revealed that NFSC contain approx. 2-fold greater concentrations of GSH when compared to CFSC and that following 4-HNE treatment, GSH levels were rapidly depleted from both cell lines. Concomitant with 4-HNE mediated GSH depletion, a corresponding increase in the 4-HNE-glutathione adduct formation was observed with the NFSC line forming greater amounts of the glutathione adduct than did the CFSC line. Taken together, these data demonstrate that both stellate cell lines have the capacity to metabolize 4-HNE but that CFSC have a greater rate of metabolism which is attributable to their greater ALDH activity, suggesting that the stellate cells isolated from cirrhotic liver may be differentially responsive to the biologic effects of 4-HNE.



Gene-Chemical Interaction Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
GSTA4Human(E)-4-hydroxynon-2-enal affects bindingISOGsta4 (Rattus norvegicus)(E)-4-hydroxynon-2-enal binds to Gsta4 proteinRGD 
GSTP1Human(E)-4-hydroxynon-2-enal affects bindingISOGstp1 (Rattus norvegicus)(E)-4-hydroxynon-2-enal binds to Gstp1 protein RGD 
Gsta4Mouse(E)-4-hydroxynon-2-enal affects bindingISOGsta4 (Rattus norvegicus)(E)-4-hydroxynon-2-enal binds to Gsta4 proteinRGD 
Gsta4Rat(E)-4-hydroxynon-2-enal affects bindingEXP (E)-4-hydroxynon-2-enal binds to Gsta4 proteinRGD 
Gstp1Rat(E)-4-hydroxynon-2-enal affects bindingEXP (E)-4-hydroxynon-2-enal binds to Gstp1 protein RGD 
Gstp1Mouse(E)-4-hydroxynon-2-enal affects bindingISOGstp1 (Rattus norvegicus)(E)-4-hydroxynon-2-enal binds to Gstp1 protein RGD 
GSTA4Human1-chloro-2,4-dinitrobenzene affects bindingISOGsta4 (Rattus norvegicus)1-chloro-2 4-dinitrobenzene binds to Gsta4 proteinRGD 
GSTP1Human1-chloro-2,4-dinitrobenzene affects bindingISOGstp1 (Rattus norvegicus)1-chloro-2 and 4-dinitrobenzene binds to Gstp1 protein RGD 
Gsta4Rat1-chloro-2,4-dinitrobenzene affects bindingEXP 1-chloro-2 4-dinitrobenzene binds to Gsta4 proteinRGD 
Gsta4Mouse1-chloro-2,4-dinitrobenzene affects bindingISOGsta4 (Rattus norvegicus)1-chloro-2 4-dinitrobenzene binds to Gsta4 proteinRGD 
Gstp1Rat1-chloro-2,4-dinitrobenzene affects bindingEXP 1-chloro-2 and 4-dinitrobenzene binds to Gstp1 protein RGD 
Gstp1Mouse1-chloro-2,4-dinitrobenzene affects bindingISOGstp1 (Rattus norvegicus)1-chloro-2 and 4-dinitrobenzene binds to Gstp1 protein RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Gsta4Rattoxic substance binding  IPI(E)-4-hydroxynon-2-enal RGD 
Gstp1Rattoxic substance binding  IPI(E)-4-hydroxynon-2-enal RGD 

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations


  
Objects Annotated

Genes (Rattus norvegicus)
Gsta4  (glutathione S-transferase alpha 4)
Gstp1  (glutathione S-transferase pi 1)

Genes (Mus musculus)
Gsta4  (glutathione S-transferase, alpha 4)
Gstp1  (glutathione S-transferase, pi 1)

Genes (Homo sapiens)
GSTA4  (glutathione S-transferase alpha 4)
GSTP1  (glutathione S-transferase pi 1)


Additional Information