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1. |
HumanCYP1B1 Leu432Valgene polymorphism: ethnic distribution in African-Americans, Caucasians and Chinese; oestradiol hydroxylase activity; and distribution in prostate cancer cases and controls |
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Pharmacogenetics,
Volume 10,
Issue 9,
2000,
Page 761-766
Yong Tang,
Bridgett Green,
Gen-Fu Chen,
Patricia Thompson,
Nicholas Lang,
Abhijit Shinde,
Dong-Xin Lin,
Wen Tan,
Beverly Lyn-Cook,
George Hammons,
Fred Kadlubar,
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摘要:
Cytochrome P4501B1 (CYP1B1) is involved in the activation of many carcinogens and in the metabolism of steroid hormones, including 17β-oestradiol (E2) and testosterone. We report a significant difference in the allele frequencies of two point mutations in the coding region of theCYP1B1gene among Caucasian (n= 189), African-American (n= 52) and Chinese (Linxian) (n= 109) populations. A (C to G) transversion at position 1666 in exon 3, which results in an amino acid substitution of Leu432to Val, was present in African-Americans with an allele frequency for Val432of 0.75, in Caucasians of 0.43, and in Chinese of 0.17. A (C to T) transition at position 1719 in exon 3, with no amino acid change (Asp449), appeared to be closely linked with the Val432variant. Results using human lung microsomal preparations from individuals with theCYP1B1Val/ValandCYP1B1Leu/Leugenotypes indicate thatVal432variant may be a high activity allele and thus may contribute to the inter-individual differences inCYP1B1activity. Because CYP1B1 is involved in hormone and carcinogen metabolism, and given the disparate rates of prostate cancer among ethnic groups, we also evaluated the association of theCYP1B1Leu432Val polymorphism with prostate cancer risk in a pilot case–control study. Among Caucasians, 34% of men with cancer (n= 50) were homozygous for the Val432polymorphism, while only 12% of matched control subjects (n= 50) had this genotype. These preliminary data indicate that genetic polymorphisms in CYP1B1 might play an important role in human prostate carcinogenesis.
ISSN:0960-314X
出版商:OVID
年代:2000
数据来源: OVID
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2. |
Catalytic efficiency determines thein-vivoefficacy of PON1 for detoxifying organophosphorus compounds |
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Pharmacogenetics,
Volume 10,
Issue 9,
2000,
Page 767-779
Wan-Fen Li,
Lucio Costa,
Rebecca Richter,
Tamara Hagen,
Diana Shih,
Aaron Tward,
Aldon Lusis,
Clement Furlong,
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摘要:
Human paraoxonase (PON1) is a polymorphic, high-density lipoprotein (HDL)-associated esterase that hydrolyzes the toxic metabolites of several organophosphorus (OP) insecticides and nerve agents. The activity polymorphism is determined by a Gln/Arg (Q/R) substitution at position 192. Injection of purified PON1 protects animals from OP poisoning. In the present study, we investigated thein-vivofunction of PON1 for detoxifying organophosphorus insecticides inPON1-knockout mice that were challenged via dermal exposure with diazoxon, diazinon and paraoxon.PON1-knockout mice were extremely sensitive to diazoxon. Doses (2 and 4 mg/kg) that caused no cholinesterase (ChE) inhibition in wild-type mice were lethal to the knockout mice, which also showed slightly increased sensitivity to the parent compound diazinon. Surprisingly, these knockout mice did not show increased sensitivity to paraoxon.In-vitroassays indicated that the PON1R192isoform hydrolyzed diazoxon less rapidly than did the PON1Q192isoform.In-vivoanalysis, wherePON1-knockout mice received the same amount of either PON1192isoform via intraperitoneal (i.p.) injection 4 h prior to exposure, showed that both isoforms provided a similar degree of protection against diazoxon, while PON1R192conferred better protection against chlorpyrifos–oxon than PON1Q192. Injection of purified rabbit PON1 or either human PON1192isoform did not protectPON1-knockout mice from paraoxon toxicity, nor did over-expression of the humanPON1R192transgene in wild-type mice. Kinetic analysis of the two human PON1192isoforms revealed that the catalytic efficiency (Vmax/Km) determines thein-vivoefficacy of PON1 for organophosphorus detoxication. The results indicate that PON1 plays a major role in the detoxication of diazoxon and chlorpyrifos oxon but not paraoxon.
ISSN:0960-314X
出版商:OVID
年代:2000
数据来源: OVID
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3. |
Genetic polymorphisms of biotransformation enzymes: allele frequencies in the population of the Czech Republic |
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Pharmacogenetics,
Volume 10,
Issue 9,
2000,
Page 781-788
Jana Šarmanová,
Lucie Týnková,
Simona Šüsová,
Ivan Gut,
Pavel Soucek,
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摘要:
Polymerase chain reaction-restriction fragment length polymorphism based genotyping assays were used to determine the frequency of polymorphisms inCYP1A1(3′-flanking region),CYP2E1(5′-flanking region and intron 6),EPHX(exon 3 and exon 4),GSTM1(deletion),GSTP1(exon 5) andGSTT1(deletion) in a group of 416 Czech individuals. A comprehensive overview of the methodology is also presented. We have found the following frequencies of mutated alleles:CYP1A1-m2, 0.097;CYP2E1-C, 0.077;CYP2E1-c2, 0.023;EPHX(exon 3)-His, 0.381;EPHX(exon 4)-Arg, 0.198;GSTM1-null, 0.51;GSTP1-Val, 0.3;GSTT1-null, 0.164. These values are similar to those presented in the majority of studies on European Caucasians, although a few cases of significant differences in the distribution of genotypes were found. These differences were most probably caused by methodological variations or statistical bias in the analyses of low numbers of samples in the control groups of some authors. Based on the results ofEPHXgenotyping, the activity of its protein product was deduced and the Czech population was divided into three subgroups with low, medium and high EPHX activity. We found that 43% of the Czech population would fall into the low, 44% into the medium and 13% into the high EPHX activity group. The data obtained may prove to be very useful for epidemiological studies on the influence of genetic polymorphisms of biotransformation enzymes on carcinogenesis or other environment-related diseases.
ISSN:0960-314X
出版商:OVID
年代:2000
数据来源: OVID
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4. |
Relationship of phenol sulfotransferase activity (SULT1A1) genotype to sulfotransferase phenotype in platelet cytosol |
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Pharmacogenetics,
Volume 10,
Issue 9,
2000,
Page 789-797
Susan Nowell,
Christine Ambrosone,
Shogo Ozawa,
Stewart MacLeod,
Gabriella Mrackova,
Suzanne Williams,
Jason Plaxco,
Fred Kadlubar,
Nicholas Lang,
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摘要:
Sulfation catalysed by human cytosolic sulfotransferases is generally considered to be a detoxification mechanism. Recently, it has been demonstrated that sulfation of heterocyclic aromatic amines by human phenol sulfotransferase (SULT1A1) can result in a DNA binding species. Therefore, sulfation capacity has the potential to influence chemical carcinogenesis in humans. To date, one genetic polymorphism (Arg213His) has been identified that is associated with reduced platelet sulfotransferase activity. In this study, data on age, race, gender, SULT1A1 genotype and platelet SULT1A1 activity were available for 279 individuals. A simple colorimetric phenotyping assay, in conjunction with genotyping, was employed to demonstrate a significant correlation (r= 0.23,P< 0.01) ofSULT1A1genotype and platelet sulfotransferase activity towards 2-naphthol, a marker substrate for this enzyme. There was also a difference in mean sulfotransferase activity based on gender (1.28 nmol/min/mg, females; 0.94 nmol/min/mg, males,P= 0.001). DNA binding studies using recombinantSULT1A1*1andSULT1A1*2revealed thatSULT1A1*1catalysedN-hydroxy-aminobiphenyl (N-OH-ABP) DNA adduct formation with substantially greater efficiency (5.4 versus 0.4 pmol bound/mg DNA/20 min) than theSULT1A1*2variant. A similar pattern was observed with 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5b]pyridine (N-OH-PhIP) (4.6 versus 1.8 pmol bound/mg DNA/20 min).
ISSN:0960-314X
出版商:OVID
年代:2000
数据来源: OVID
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5. |
Compound heterozygosity for missense mutations in the flavin-containing monooxygenase 3 (FMO3) gene in patients with fish-odour syndrome |
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Pharmacogenetics,
Volume 10,
Issue 9,
2000,
Page 799-807
Colin Dolphin,
Azara Janmohamed,
Robert Smith,
Elizabeth Shephard,
Ian Phillips,
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摘要:
Fish-odour syndrome is a highly unpleasant disorder of hepatic trimethylamine (TMA) metabolism characterized by a body odour reminiscent of rotting fish, due to excessive excretion of the malodorous free amine. Although fish-odour syndrome may exhibit as sequelae with other conditions (e.g. liver dysfunction), many patients exhibit an inherited, more persistent form of the disease. Ordinarily, dietary-derived TMA is oxidized to the non-odorousN-oxide by hepatic flavin-containing monooxygenase 3 (FMO3). Our previous demonstration that a mutation, P153L (C to T), in theFMO3gene segregated with the disorder and inactivated the enzyme confirmed that defects inFMO3underlie the inherited form of fish-odour syndrome. We have investigated the genetic basis of the disorder in two further affected pedigrees and report that the three propositi are all compound heterozygotes for causative mutations ofFMO3. Two of these individuals possess the P153L (C to T) mutation and a novel mutation, N61S (A to G). The third is heterozygous for novel, M434I (G to A), and previously reported, R492W (C to T), mutations. Functional characterization of the S61, I434 and W492 variants, via baculovirus-mediated expression in insect cells, confirmed that all three mutations either abolished, or severely attenuated, the capacity of the enzyme to catalyse TMAN-oxidation. Although I434 and W492 were also incapable of catalysing theS-oxidation of methimazole, S61 was fully active with this sulphur-containing substrate. Since an asparagine is conserved at the equivalent position to N61 of FMO3 in mammalian, yeast andCaenorhabditis elegansFMOs, the characterization of the naturally occurring N61S (A to G) mutation may have identified this asparagine as playing a critical role specifically in FMO-catalysedN-oxidation.
ISSN:0960-314X
出版商:OVID
年代:2000
数据来源: OVID
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6. |
Tissue specific differences in the regulation of the UDP glucuronosyltransferase 2B17 gene promoter |
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Pharmacogenetics,
Volume 10,
Issue 9,
2000,
Page 809-820
Philip Gregory,
Antony Hansen,
Peter Mackenzie,
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摘要:
The human UDP glucuronosyltransferase UGT2B17, glucuronidates androgens and is expressed in the liver and the prostate. Although evidence suggests that variations in UGT2B17 expression between tissues may be a critical determinant of androgen response, the factors that regulate UGT2B17 expression in the liver and prostate are unknown. In this study, we have isolated a 596 bp promoter of theUGT2B17gene and studied its regulation in the liver cell line, HepG2 and the prostate cell line, LNCaP. The transcription start site ofUGT2B17was mapped and proteins that bound to the proximal promoter were detected by DNase1 footprint analysis. A region (−40 to −52 bp) which resembled a hepatocyte nuclear factor 1 (HNF1) binding site bound proteins in nuclear extracts from HepG2 cells, but did not bind proteins from LNCaP nuclear extracts. In HepG2 cells, HNF1α bound to this region and activated theUGT2B17promoter, as assessed by functional and gel shift assays. HNF1α activation of the promoter was prevented by mutation or deletion of the putative HNF1 site. The related transcription factor HNF1β, which is present in HepG2 cells, did not activate the promoter. TheUGT2B17promoter could also be activated by exogenous HNF1α in LNCaP cells. However, because these cells do not contain HNF1α, other transcription factors must regulate theUGT2B17promoter. Cotransfection experiments showed that HNF1β elevates promoter activity in LNCaP cells. This activation did not involve the putative HNF1 region (−40 to −52 bp) since mutation of this region did not affect promoter activation by HNF1β. These results suggest that theUGT2B17promoter is regulated by different factors in liver-derived HepG2 and prostate-derived LNCaP cells.
ISSN:0960-314X
出版商:OVID
年代:2000
数据来源: OVID
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7. |
Prospective evaluation of detoxification pathways as markers of cutaneous adverse reactions to sulphonamides in AIDS |
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Pharmacogenetics,
Volume 10,
Issue 9,
2000,
Page 821-828
Pierre Wolkenstein,
Marie-Anne Loriot,
Selim Aractingi,
Arnaud Cabelguenne,
Philippe Beaune,
Olivier Chosidow,
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摘要:
The use of sulphonamides is complicated by a high rate of cutaneous reactions in AIDS. Metabolic risk factors have been suspected for these reactions. We conducted a prospective study to evaluate whether glutathioneS-transferase M1 null genotype, glutathione deficiency and acetylator status as risk factors. To explain the high frequency of slow acetylator phenotype in AIDS patients, we comparedN-acetyltransferase-2 phenotype and genotype in this population. AIDS patients treated with sulphonamides forPneumocystis cariniipneumonia or toxoplasmosis were followed up for cutaneous reactions. GlutathioneS-transferase genotyping, glutathione level determination,N-acetyltransferase-2 genotyping and phenotyping were performed. One hundred and thirty-six AIDS patients were studied. GlutathioneS-transferase M1 and T1 null genotypes, intracellular glutathione level, slow acetylator genotype and phenotype were not risk factors for cutaneous sulphonamides reactions. The association of glutathioneS-transferase M1 null genotype and the slow acetylator one was a risk factor [Fisher's exact test, odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.2–5.9;P= 0.02]. A discordance between acetylator genotype and phenotype was found in 35% of patients. This frequency was significantly higher than the 6–7% expected (Fisher's exact test: OR = 7.5, 95% CI = 4.2–13.4;P<0.0001). Suspected metabolic risk factors for sulphonamides cutaneous reactions were not confirmed prospectively. However, the association of glutathioneS-transferase M1 null genotype and the slow acetylator one appeared to increase the risk of reactions. We clearly showed that the acetylation phenotype measured by caffeine probe could be modified by the disease.
ISSN:0960-314X
出版商:OVID
年代:2000
数据来源: OVID
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8. |
Distribution of theN-oxidation of dietary-derived trimethylamine in a male Chinese population |
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Pharmacogenetics,
Volume 10,
Issue 9,
2000,
Page 829-831
C. Lee,
B. Tomlinson,
J. Yeung,
G. Lin,
L. Damani,
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ISSN:0960-314X
出版商:OVID
年代:2000
数据来源: OVID
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