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1. |
Predicting the cytochrome P450 mediated metabolism of xenobiotics |
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Pharmacogenetics,
Volume 3,
Issue 1,
1993,
Page 1-18
Kenneth Korzekwa,
Jeffery Jones,
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摘要:
The cytochrome P450s play a unique role in the metabolism of xenobiotics. Characteristics which allow a vast number of foreign compounds to be metabolized by a limited number of enzymes include broad substrate specificity and broad regioselectivity. Because of their importance in both the metabolism and toxicity of drugs and environmental contaminants, efforts are being made to use computational methods to predict these biotransformation pathways. This review describes the recent progress towards the prediction of the tertiary structures of the various P450s and the determination of the electronic characteristics of substrates which determine their tendency to be oxidized by the P450s.
ISSN:0960-314X
出版商:OVID
年代:1993
数据来源: OVID
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2. |
PCR-basedCYP2D6genotyping for Finnish lung cancer patients |
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Pharmacogenetics,
Volume 3,
Issue 1,
1993,
Page 19-27
Ari Hirvonen,
Kirsti Husgafvel-Pursiainen,
Sisko Anttila,
Antti Karjalainen,
Olavi Pelkonen,
Harri Vainio,
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摘要:
Polymorphism of the gene encoding for debrisoquine hydroxylase,i.e.CYP2D6, was determined genotypically for 122 healthy controls and 106 lung cancer patients usingXbaI restriction fragment length polymorphism (RFLP) analysis, together with a combination of two recently published polymerase chain reaction (PCR) based approaches. Three different mutated alleles of theCYP2D6gene were detected;CYP2D6Bcomprised 11.1% and 10.4% of the total alleles in the controls and in the lung cancer patients,CYP2D6Ahad frequencies of 5.7% and 2.8%, andCYP2D6Dhad frequencies of 3.3% and 2.4%, respectively. Only 17 of the 24 44 kbXbaI alleles (71%) were confirmed as defective alleles carrying the mutation in CYP2D6B loci, whereas all four 15 + 9 kbXbaI alleles contained theCYP2D6Bmutation. Out of the 122 healthy controls, seven subjects (5.7%) were detected as poor metabolizers (PMs) of debrisoquine by the presence of two defective alleles, whereas only one PM genotype was found in the lung cancer patient group (0.9%). The reliability of this analysis was confirmed in a subgroup of the control subjects phenotyped by debrisoquine, where a perfect correlation betweenCYP2D6phenotype and genotype was obtained. We observed no significant difference in the allelic frequencies between lung cancer patients with a history of heavy smoking and those who smoked less. However, statistical analysis showed a significant difference (p=0.05) in distribution of the PM-associated genotypes between lung cancer patients (1/106) and healthy controls (7/122). This data thus supports the hypothesis that there is an increased risk of lung cancer for individuals who are extensive metabolizers of debrisoquine.
ISSN:0960-314X
出版商:OVID
年代:1993
数据来源: OVID
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3. |
Characterization of a human cell line expressing high levels of cDNA-derived CYP2D6 |
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Pharmacogenetics,
Volume 3,
Issue 1,
1993,
Page 28-39
B W Penman,
J Reece,
T Smith,
C S Yang,
H V Gelboin,
F J Gonzalez,
C L Crespi,
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摘要:
We have developed a human B-lymphoblastoid cell, designated h2D6v2, which expresses high levels of CYP2D6 cDNA. Microsomal P450 contents of 160 pmol mg-1protein were observed. NADPH fortified microsomes exhibited a substantial capacity to hydroxylate the prototype CYP2D6 substrates bufuralol and debrisoquine. Kinetic parameters, apparent Km, turnover number, Kifor quinidine inhibition and stereospecificity of bufuralol hydroxylation, observed with the human lymphoblast expressed enzyme were similar to those observed in human liver microsomes or purified liver CYP2D6 proteins. Therefore, the human lymphoblast expressed material appears to faithfully reflect the authentic protein. Relative to control cells, h2D6v2 cells were more sensitive to the cytotoxicity and mutagenicity of 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK), supporting our previous observation with a cell line expressing lower levels of CYP2D6. h2D6v2 microsomes were capable of metabolizing NNK and NNK metabolism and mutagenicity were markedly inhibited by the addition of quinidine, a CYP2D6 inhibitor. h2D6v2 cells coupled with control cells, represent a usefulin vitrosystem for studying xenobiotic metabolism by the clinically important, polymorphic CYP2D6. The human lymphoblast system offers the desirable ability to couple metabolic transformation studies with toxicological endpoints such as cytotoxicity and mutagenicity.
ISSN:0960-314X
出版商:OVID
年代:1993
数据来源: OVID
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4. |
Molecular genetics of the flavin-dependent monooxygenases |
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Pharmacogenetics,
Volume 3,
Issue 1,
1993,
Page 40-44
Michael Lawton,
Richard Philpot,
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ISSN:0960-314X
出版商:OVID
年代:1993
数据来源: OVID
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5. |
Molecular genetics of the N-acetyltransferases |
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Pharmacogenetics,
Volume 3,
Issue 1,
1993,
Page 45-50
Denis Grant,
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ISSN:0960-314X
出版商:OVID
年代:1993
数据来源: OVID
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6. |
Regulation of cytochrome P450 genes: molecular mechanisms |
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Pharmacogenetics,
Volume 3,
Issue 1,
1993,
Page 51-57
Frank Gonzalez,
Su-Yan Liu,
Masahiko Yano,
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PDF (566KB)
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摘要:
The xenobiotic-metabolizing cytochrome P450s are found in the CYP1, CYP2, CYP3 and CYP4 subfamilies (Gonzalez, 1988). These P450s have been extensively studied in a number of organisms including bacteria, yeast, fish, chickens, rats, mice, rabbits and humans. The P450 genes are under control of diverse regulatory networks that govern their expression. These networks include foreign chemical receptors that activate gene expression through binding to inducible enhancer elements and tissue-enriched transcription factors that control constitutive expression. This review focuses on recent developments on the molecular mechanisms of P450 gene control.
ISSN:0960-314X
出版商:OVID
年代:1993
数据来源: OVID
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7. |
The misuse of urinary metabolite excretion data in drug metabolism studies |
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Pharmacogenetics,
Volume 3,
Issue 1,
1993,
Page 58-59
John Miners,
Donald Birkett,
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PDF (143KB)
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ISSN:0960-314X
出版商:OVID
年代:1993
数据来源: OVID
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8. |
Utilizing urinary metabolite data in studying the variability of acetaminophen metabolism |
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Pharmacogenetics,
Volume 3,
Issue 1,
1993,
Page 60-60
M Patel,
B-K Tang,
W Kalow,
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PDF (91KB)
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ISSN:0960-314X
出版商:OVID
年代:1993
数据来源: OVID
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