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1. |
Editorial |
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Pharmacogenetics,
Volume 2,
Issue 1,
1992,
Page 1-1
Jeff Idle,
Frank Gonzalez,
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ISSN:0960-314X
出版商:OVID
年代:1992
数据来源: OVID
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2. |
Clinical implications of variable antiarrhythmic drug metabolism |
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Pharmacogenetics,
Volume 2,
Issue 1,
1992,
Page 2-11
Elaine Buchert,
Raymond Woosley,
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摘要:
Due to their narrow therapeutic indices, antiarrhythmic drugs have a great potential for adverse outcome. This is amplified by extreme inter-individual variability in their disposition and their pharmacological actions. Genetically determined inter-individual differences in metabolism account for a great deal of this variability. However, because of active metabolites, chirally-specific actions and chirally-specific metabolism, it is not possible to generalize about the outcome of phenotypic differences in the metabolism of a given drug. Careful study of these factors can enable physicians to understand the spectrum of potential responses to a drug. Newly developed molecular biology techniques now make it possible to determine the genotype for the CYP2D6 gene that controls metabolism of many antiarrhythmic drugs. This information, combined with a full understanding of the drugs' clinical pharmacology now makes it possible to predict the clinical outcome for drugs such as encainide, flecainide, mexiletine, propafenone and combinations of these drugs with quinidine.
ISSN:0960-314X
出版商:OVID
年代:1992
数据来源: OVID
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3. |
Effects of ethanol, dexamethasone and RU 486 on expression of cytochromes P450 2B, 2E, 3A and glutathione transferase π in a rat hepatoma cell line (Fao) |
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Pharmacogenetics,
Volume 2,
Issue 1,
1992,
Page 12-18
I de Waziers,
J Bouguet,
P H Beaune,
F J Gonzalez,
B Ketterer,
R Barouki,
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摘要:
The aim of our study was to investigate the suitability of Fao cells, derived from the Reuber H3 5 rat hepatoma as a tool for studying regulation of drug-metabolizing enzymes and drug metabolism. Fao cells express P450 2B, 2E, 3A and GST π and were used to study the effects of different inducers on these enzymes. Ethanol considerably increased the amounts of P450 2E and, to a lesser extent, P450 2B and GST π mRNA and protein. Dexamethasone decreased the amounts of P450 2B, 3A and GST π mRNAs, but had no appreciable effect per se upon the protein concentration of these enzymes. However, it antagonized the induction of P450 2E, 2B and GST π by ethanol, even at the protein level. RU 486 decreased P450 2B protein and P450 2E mRNA and protein levels without effecting P450 3A and GST π expression. RU 486 did not antagonize the dexamethasone effects, suggesting that at least some of these effects are not mediated by the glucocorticoid receptor. These data indicate that these cells constitute a suitable tool for studying the regulation of drug-metabolizing enzyme expression and drug metabolism.
ISSN:0960-314X
出版商:OVID
年代:1992
数据来源: OVID
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4. |
Deficient nifedipine oxidation: a rare inherited trait associated with cystic fibrosis kindreds |
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Pharmacogenetics,
Volume 2,
Issue 1,
1992,
Page 19-24
Ann Daly,
Baljinder Salh,
Diana Bilton,
Judith Allen,
Alastair Knight,
A Kevin Webb,
Joan Braganza,
Jeffrey Idle,
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摘要:
Previous studies have indicated that there is weak genetic linkage between the defective gene in cystic fibrosis (CFTR) and the gene encoding the nifedipine metabolizing enzyme P4503A4 which are both located on chromosome 7. To examine further this possible association, nifedipine metabolism was investigated in a group of 59 volunteers, and 17 adult cystic fibrosis patients and 37 of their relatives. In agreement with the majority of previous studies, the volunteer group showed a unimodal distribution of recoveries for the major metabolite M-II ranging from 33 to 78% excretion in 8 h. In the case of both the cystic fibrosis patients and their parents, the distribution of recoveries was shifted to the left with five out of 20 parents and three out of 11 unrelated cystic fibrosis patients showing recoveries below the range observed in the volunteer group. This poor metabolism appeared to be both reproducible and heritable and did not appear to be a consequence of mutations in the CFTR gene.
ISSN:0960-314X
出版商:OVID
年代:1992
数据来源: OVID
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5. |
Polymorphic hydroxylation of S-mephenytoin and omeprazole metabolism in Caucasian and Chinese subjects |
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Pharmacogenetics,
Volume 2,
Issue 1,
1992,
Page 25-31
Tommy Andersson,
Carl-Gunnar Regårdh,
Ya-Ching Lou,
Yuan Zhang,
Marja-Liisa Dahl,
Leif Bertilsson,
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摘要:
Twelve Caucasian healthy men and women, of whom six were poor metabolizers (PMs) and six were extensive metabolizers (EMs) of S-mephenytoin, together with 13 Chinese healthy men and women (five PMs and eight EMs), received a single oral 20 mg dose of omeprazole. Plasma levels of omeprazole and its two main metabolites, omeprazole sulphone and hydroxyomeprazole, were determined by HPLC.The mean ( + SD) area under the plasma concentration-time curve (AUC) for omeprazole was 11.1 ±2.6 and 0.9 ± 0.4 μM h in the Caucasian PMs and EMs, respectively. Corresponding values for elimination half-life were 2.3 ± 0.4 and 0.7 ± 0.4 h. In the Chinese PMs and EMs the AUC of omeprazole as 13.3 + 5.6 and 2.6 ± 1.8 μM h. The AUCs of omeprazole were significantly higher in the Chinese EMs than in the Caucasian EMs possibly due to the higher proportion of heterozygotes in the former than in the latter group. The elimination half-life in the Chinese PMs and EMs was 2.4 ± 0.2 and 0.8 + 0.2 h -similar to the observations in the Caucasian subjects. The maximum plasma concentration of hydroxyomeprazole was five-fold and four-fold higher in EMs compared to PMs among Caucasians and Chinese, respectively. The elimination half-life of the hydroxy metabolite was also longer in PMs than in EMs in both populations. The ratio between AUC for omeprazole and AUC for hydroxyomeprazole was 11.9 ± 2.1 and 0.6 + 0.1 in Caucasian PMs and EMs, respectively. Corresponding values in the Chinese were 13.1 ±2.9 and 1.6 + 0.5. The AUCs of the sulphone metabolite were higher in PMs than in EMs among both Caucasians and Chinese. A longer half-life of the sulphone was also found in PMs compared to EMs.It is concluded that a major metabolic pathway of omeprazole, the formation of hydroxyomeprazole and at least partly also its elimination, cosegregates with the polymorphic metabolism of S-mephenytoin in both Caucasians and Chinese. The elimination, and perhaps part of the formation, of omeprazole sulphone also appears to be dependent on this polymorphic enzyme.
ISSN:0960-314X
出版商:OVID
年代:1992
数据来源: OVID
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6. |
Molecular characterization of the murine Coh locus: an amino acid difference at position 117 confers high and low coumarin 7-hydroxylase activity in P450coh |
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Pharmacogenetics,
Volume 2,
Issue 1,
1992,
Page 32-37
R L P Lindberg,
R Juvonen,
M Negishi,
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摘要:
Coumarin 7-hydroxylase (P450coh) and steroid 15a-hydroxylase (P45015a) are encoded by members within the mouse 2A subfamily. Since P450coh activity is regulated by the Coh locus, we characterized P450coh cDNAs in strains having high coumarin 7-hydroxylase activity (CohHhomozygote) including 129/J and DBA/2J, and compared them with P450coh cDNAs in low activity strains (CohL homozygote) C57BL/6J, C3H/HeJ and AKR/J. The nucleotide sequences of these two cDNAs differ by a single base, which results in an amino acid difference at position 117 (Val in P450cohHand Ala in P450cohL). The CohHphenotype exhibits approximately 10-fold greater Vmaxand four-fold lower Km values than those in the CohL. Male 129AKF1/J expresses approximately equal amounts of P450cohHand P450cohLmRNAs, associated with two Coh alleles. The levels of P450coh and P45015xmRNAs in the F1offspring suggested that a trans -acting factor(s) appeared to regulate the expressions of the P450 genes. A recent duplication in the ancestral mouse established the line of descent to P45015xfrom the ancestral P450coh gene. During evolution, amino acid substitutions have selectively occurred at positions which alter the enzyme's substrate specificity and increase in the specific activity. Consistent with an important role of natural selection in the evolution of these genes is the relatively high nonsynonomous substitution rates on the P45O15a and the P450coh branches. As a result of these evolution events, the gene family consists of members which exhibit an extremely high degree of structural similarity, but very divergent hydroxylase activities and modes of regulation.
ISSN:0960-314X
出版商:OVID
年代:1992
数据来源: OVID
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7. |
Variability of acetaminophen metabolism in Caucasians and Orientals |
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Pharmacogenetics,
Volume 2,
Issue 1,
1992,
Page 38-45
M Patel,
B K Tang,
W Kalow,
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摘要:
Acetaminophen (paracetamol) is extensively conjugated with glucuronic acid and sulfate prior to renal excretion. A minor metabolic route involves microsomal oxidation of acetaminophen to a hepatotoxic reactive intermediate, which subsequently undergoes glutathione (GSH) conjugation, yielding cysteine and mercapturate conjugates, both of which are excreted in the urine (Slattery et al., 1987). Data collected by de Morais et al. (1989) indicated that in comparison with normal subjects, glucuronidation of acetaminophen was impaired in subjects with Gilbert's syndrome, a genetically-based impairment of bilirubin glucuronidation. Thus, inter-subject and ethnic differences in acetaminophen disposition have pharmacogenetic and toxicological implications. This study was conceived to explore these differences.Urinary excretion of acetaminophen and its metabolites was observed in 125 Caucasian and 33 Oriental subjects. No appreciable difference was noted in the mean fraction of drug excreted as glucuronide between the two groups (51.5% in Caucasians vs 51.8% in Orientals). However, the data strongly indicated that the excretion of acetaminophen glucuronide was not normally distributed. Bimodality was apparent in both groups, with 20% of Caucasian and 33% of Oriental subjects displaying relatively extensive glucuronidation. In addition, glucuronidation displayed a strong negative correlation with sulfation (r=— 0.97), suggesting the existence of a compensatory mechanism between the two metabolic pathways.The mean fractional excretions of cysteine and mercapturate conjugates did show significant differences between Caucasians and Orientals (p<0.005). In addition, the ratio of mercapturate to total GSH-derived conjugates recovered appeared to be bimodal, indicating possible heterogeneity in the conversion of the cysteine conjugate to mercapturate via N-acetylation.
ISSN:0960-314X
出版商:OVID
年代:1992
数据来源: OVID
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