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1. |
Jun and Fos regulation of NAD(P)Hquinone oxidoreductase gene expression |
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Pharmacogenetics,
Volume 4,
Issue 1,
1994,
Page 1-10
Anil Jaiswal,
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摘要:
NAD(P)H:Quinone oxidoreductase, (NQO1) is a flavoprotein which promotes obligatory two-electron reduction of quinones, preventing their participation in redox cycling, oxidative stress and neoplasia. High levels of NQO1have been observed in several kinds of tumours including that of the liver, lung, colon and breast. Transcription of the NQO1gene is increased in response to bifunctional [e.g. β-naphthoflavone (β-NF), 2,3,7,8,-tetrachlordibenzo-p-dioxin (dioxin)] and monofunctional [phenolic antioxidants/chemoprotectors e.g. 2(3)tert-butyl-4-hydroxy-anisole (BHA)] inducers. High basal expression of the NQO1gene and its induction by β-NF and BHA are mediated by 31 bp of the antioxidant response element (ARE) containing more than one copy of the Aβ1/Aβ1-like binding sites, Jun and Fos and other(s) as yet unknown regulatory proteins. The arrangement of Aβ1 /Aβ1 -like elements within a short region of DNA may be important for β-NF and BHA response. The high basal expression of the NQO1gene in several types of tumour tissues may be due to a high expression and/or modification of regulatory proteins that result from tumour formation. Signal transduction from β-NF and BHA for increased expression of the NQO1gene involve metabolism of β-NF and generation of 'redox signals'. The sequence of events after generation of 'redox signals' leading to the modification/activation of regulatory proteins that bind to ARE and increase expression of the NQO1gene are less clear. The possibilities include involvement of protein(s) which receive signals from β-NF and BHA and modulate the Jun and Fos proteins for increased binding to the ARE element or increased activities of the transcriptional activation domains of the regulatory proteins. The modifications in the regulatory proteins may be reduction of a cysteine residue in the DNA binding domain and/or phosphorylation of the DNA binding/transcriptional activation domains. Further studies are required to identify the intermediary components in the signal transduction pathway to completely understand the mechanism of induction of the NQO1gene expression in response to β-NF and BHA.Dioxin induction of the NQO1gene expression is mediated by XRE, an element best characterized in the case of the CYP1A1 gene. As seen for the CYP1A1 gene, dioxin induction of NQO1gene expression may involve binding of dioxin to the Ah receptor, release of the Hsp90 protein associated with the cytosolic Ah receptor, phosphorylation of Ah receptor by protein kinase C (PKC), heterodimerization with Arnt (phosphorylated by PKC?), nuclear translocation of dioxin-Ah, receptor-Arnt complex, binding at XRE element in the promoter region of the NQO1gene resulting in activation of the NQO1gene. The mechanism involving the Ah receptor and XRE may also be responsible in part for the β-NF induction of the NQO1gene expression. This is because β-NF could bind to the Ah receptor, though at a much lower affinity as compared to dioxin. Similarly, it will be interesting to determine if dioxin induction of the NQO12gene expression also involves the ARE element and Jun and Fos proteins. Indeed dioxin has been reported to increase the expression of the c-Fos gene. The regulation of the NQO1gene is complex as several additionalcis-elements have been identified in its promoter. Several other genes of phase II metabolism enzymes including glutathione-S-transferase, UDPG-transferase and perhaps epoxide hydrolase are expected to be co-ordinately regulated by mechanisms involving one or more ARE and XRE elements and Jun and Fos and Ah receptor proteins.
ISSN:0960-314X
出版商:OVID
年代:1994
数据来源: OVID
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2. |
Selective expression of cytochrome P450 CYP3A mRNAs in embryonic and adult human liver |
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Pharmacogenetics,
Volume 4,
Issue 1,
1994,
Page 11-20
John Schuetz,
Deborah Beach,
Philip Guzelian,
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摘要:
The humanCYP3AP450 family, composed of at least four highly homologous genes, is expressed prominently in the liver. To investigate the expression ofCYP3Afamily members individually, we prepared oligonucleotides specific for each CYP3A mRNA and used Northern blot analysis and/or polymerase chain reaction to examine RNA from adult and fetal liver for variation in expression of theCYP3Aforms during development. We found that CYP3A4 (P450NF) mRNA, was only detectable by Northern blot postnatally, was highly variable (10-fold) among the adult samples, and, unlike its rat counterparts (CYP3A1/2), was not influenced by gender. In contrast, CYP3A7 (HFLa) mRNA, a form previously thought to be confined to fetal liver, was found in all tested samples of fetal liver as well as in seven of 13 adult livers (54%). CYP3A5 (HLp2), an mRNA also found in all the fetal samples, was detected in three of these 13 adults (23%) and two of these three co-expressed CYP3A7 mRNA.CYP3A5andCYP3A7are expressed at similar levels in fetal liver from either gender. Moreover,CYP3A7expression in fetal liver appears less variable (<2.5-foId) thanCYP3A4in adults. We conclude, that contrary to prevailing views, expression ofCYP3A 7in the liver is not restricted to the fetus but rather represents a second CYP3A form selectively expressed in adults.
ISSN:0960-314X
出版商:OVID
年代:1994
数据来源: OVID
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3. |
1462V mutation in the humanCYP1A1genelack of correlation with either theMspI 1.9 kb (M2) allele or CYP1A1 inducibility in a three‐generation family of East Mediterranean descent |
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Pharmacogenetics,
Volume 4,
Issue 1,
1994,
Page 21-26
Peter Wedlund,
Shioko Kimura,
Frank Gonzalez,
Daniel Nebert,
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摘要:
A 15-member three-generation family of Eastern Mediterranean descent was previously studied, and an association between CYP1A1 (cytochrome P1450, benzo[a]pyrene hydroxylase) inducibility and aCYP1A13‘-polymorphism (theMspI 1.9 kb allele) was reported (Petersenet al. Am J Hum Genet1991: 48, 720–725). Here we have re-examined the original DNA (and in some cases, newly prepared DNA from freshly drawn blood) from these same individuals, in order to assess the association between CYP1A1 inducibility and both theCYP1A1geneMspI RFLP polymorphism and theCYP1A1gene A→G polymorphism at codon 462. This latter nucleotide change results in an altered amino acid (462Ile →Val), which is purported to increase CYP1A1 enzyme activity and mutagenicity towards benzo[a]pyrene about two-fold among Japanese. Among the 15 members of this three-generation family examined, no absolute correlation was observed between the 1462V genotype and either the Msp I 1.9kb allele or the CYP1A1 inducibility phenotype. We also found no absolute correlation between theMspI 1.9 kb allele and the CYP1A1 inducibility phenotype.
ISSN:0960-314X
出版商:OVID
年代:1994
数据来源: OVID
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4. |
Stereoselective disposition of hexobarbital and its metabolitesrelationship to theS-mephenytoin polymorphism in Caucasian and Chinese subjects |
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Pharmacogenetics,
Volume 4,
Issue 1,
1994,
Page 27-38
A. Adedoyin,
C. Prakash,
D. O'Shea,
I. Blair,
G. Wilkinson,
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摘要:
In vitrostudies with human liver preparations suggest that the metabolism of hexobarbital involves CYP2CMP— the determinant of theS-mephenytoin 4‘-hydroxylation polymorphism, but no invivoevidence of interphenotypic differences exist. The pharmacokinetics and urinary excretion of hexobarbital and its metabolites were, therefore, investigated following oral administration of a differentially labelled pseudoracemate that allowed determination of the fate of the individual enantiomers. Studies were undertaken in 10 Caucasian and nine Chinese healthy subjects known to be either extensive (EM) or poor (PM), metabolizers of mephenytoin. No inter-racial differences were observed in any of the measured parameters within a given phenotype. However, pronounced stereoselectivity in disposition was noted in EMs withR-( – )-hexobarbital's oral clearance being five- to six-fold greater than that for theS-( + )-enantiomer. By contrast, theS-( + )-isomer was eliminated twice as fast asR-( — ) hexobarbital in PMs and, in addition, the oral clearances of both enantiomers were significantly reduced compared with their values in EMs. Formation of 3’-hydroxy- and 3‘-ketohexobarbital and 1,5-dimethyIbarbituric acid were the major identified routes of metabolism for each enantiomer in both phenotypes. Furthermore, these pathways were found to co-segregate with the mephenytoin polymorphism and in EMs they were primarily responsible for the observed stereoselectivity in disposition. These findings, therefore, confirm the stereoselectivity in hexobarbital's disposition in humans and identify the major pathways of metabolism involved. Additionally, the results indicate that CYP2CMPis a major determinant of the invivometabolism of both of hexobarbital's enantiomers but especially that of theR-( — )-enantiomer.
ISSN:0960-314X
出版商:OVID
年代:1994
数据来源: OVID
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5. |
Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9 |
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Pharmacogenetics,
Volume 4,
Issue 1,
1994,
Page 39-42
Allan Rettie,
Larry Wienkers,
Frank Gonzalez,
William Trager,
Kenneth Korzekwa,
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ISSN:0960-314X
出版商:OVID
年代:1994
数据来源: OVID
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6. |
Cytochrome P450‐dependent metabolism of acetaminophen in four human transgenic lymphoblastoid cell lines |
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Pharmacogenetics,
Volume 4,
Issue 1,
1994,
Page 43-46
John Snawder,
Amy Roe,
R. Benson,
Daniel Casciano,
Dean Roberts,
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PDF (286KB)
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ISSN:0960-314X
出版商:OVID
年代:1994
数据来源: OVID
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