Linked Life Data

15766272

Source:http://linkedlifedata.com/resource/pubmed/id/15766272

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
2005-3-15
pubmed:abstractText
4-Nitroquinoline 1-oxide (NQO) is a reactive electrophile with potent cytotoxic as well as genotoxic activities. NQO forms a conjugate, QO-SG, with glutathione, which greatly reduces its chemical reactivity. Previous studies demonstrated that glutathione S-transferase (GST) P1a-1a and multidrug resistance protein (MRP) 1/2 act in synergy to confer resistance to both cyto- and genotoxicities of NQO, whereas protection afforded by GSTP1a-1a or MRP alone was much less. To better understand the role of glutathione, GSTP1a-1a, and MRP1 in NQO detoxification, we have characterized the kinetics and cofactor requirements of MRP1-mediated transport of QO-SG and NQO. Additionally, using recombinant GSTP1a-1a and physiological conditions, we have examined the enzymatic and nonenzymatic formation of QO-SG. Results show that MRP1 supports efficient transport of QO-SG with a K(m) of 9.5 microM and a V(max) comparable to other good MRP1 substrates. Glutathione or its S-methyl analogue enhanced the rate of (3)H-QO-SG transport, whereas QO-SG inhibited the rate of (3)H-glutathione transport. These data favor a mechanism for glutathione-enhanced, MRP1-mediated QO-SG transport that does not involve cotransport of glutathione. NQO was not transported by MRP1 either alone or in the presence of S-methyl glutathione. Transport of (3)H-NQO was observed in the presence of glutathione, but uptake into MRP1-containing vesicles was entirely attributable to its conjugate, QO-SG, formed nonenzymatically. While the nonenzymatic rate was readily measurable, enzyme catalysis was overwhelmingly dominant in the presence of GSTP1a-1a (rate enhancement factor, (k(cat)/K(m))/k(2), approximately 3 x 10(6)). We conclude that MRP1 supports detoxification of NQO via efficient, glutathione-stimulated efflux of QO-SG. While nonenzymatic QO-SG formation and MRP1-mediated conjugate efflux result in low-level protection from cyto- and genotoxicities, this protection is greatly enhanced by coexpression of GSTP1-1 with MRP1. This result emphasizes the quantitative importance of enzyme-catalyzed conjugate formation, a crucial determinant of high-level, MRP-dependent protection of cells from NQO toxicity.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
22
pubmed:volume
44
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4426-33
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:15766272-4-Nitroquinoline-1-oxide, pubmed-meshheading:15766272-Carcinogens, pubmed-meshheading:15766272-Catalysis, pubmed-meshheading:15766272-Cell Line, Tumor, pubmed-meshheading:15766272-Glutathione, pubmed-meshheading:15766272-Glutathione S-Transferase pi, pubmed-meshheading:15766272-Glutathione Transferase, pubmed-meshheading:15766272-Humans, pubmed-meshheading:15766272-Hydrogen-Ion Concentration, pubmed-meshheading:15766272-Isoenzymes, pubmed-meshheading:15766272-Kinetics, pubmed-meshheading:15766272-Metabolic Detoxication, Drug, pubmed-meshheading:15766272-Multidrug Resistance-Associated Proteins, pubmed-meshheading:15766272-Substrate Specificity, pubmed-meshheading:15766272-Temperature, pubmed-meshheading:15766272-Thermodynamics, pubmed-meshheading:15766272-Transport Vesicles
pubmed:year
2005
pubmed:articleTitle
Dynamics of glutathione conjugation and conjugate efflux in detoxification of the carcinogen, 4-nitroquinoline 1-oxide: contributions of glutathione, glutathione S-transferase, and MRP1.
pubmed:affiliation
Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.