摘要:

To standardize CYP2D6 allele nomenclature, and to conform with international human gene nomenclature guidelines, an alternative to the current arbitrary system is described. Based on recommendations for human genome nomenclature, we propose that alleles be designated by CYP2D6 followed by an asterisk and a combination of roman letters and arabic numerals distinct for each allele with the number specifying the key mutation and, where appropriate, a letter specifying additional mutations. Criteria for classification as a separate allele and protein nomenclature are also presented.

ISSN:0960-314X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

CYP2E1 is involved in the activation of various carcinogens, including N-nitrosamines, which are believed to be important in human carcinogenesis. Humans exhibit wide interindividual variability in levels of CYP2E1 mRNA and protein, which might explain interindividual differences in susceptibility to carcinogens activated by CYP2E1. Such variability could be due either to genetic polymorphisms observed in the CYP2E1 gene (Rsa I in the 5 '-flanking region, Dra I in intron 6 and Taq I in intron 7) or to varying inducibility by xenobiotics. The aim of the present study was to establish whether, in a Caucasian population (n=93), there existed a relationship between allelic forms of the CYP2E1 gene and the phenotype determined in vitro by hepatic ability to 6-hydroxylate chlorzoxazone. Rates of chlorzoxazone- 6-hydroxylation were significantly correlated with levels of immunochemically measured CYP2E1 (p<0.001). CYP1A2,2C8,2C9,2C18,2D6,3A4 and 3A5 did not appear to be significantly involved in chlorzoxazone metabolism, whereas the participation of CYP1A1 could not be excluded. Frequencies of the rare alleles for the three polymorphism sites were 2.2% for Rsa 1,7.5% for Dra I and 8.5% for Taq I. Despite substantial interindividual variations in chlorzoxazone hydroxylase activity, no relationship between any of the three polymorphisms and CYP2E1 activity was established. Therefore, in humans, interindividual variability in CYP2E1 levels is probably due to differing induction levels as a result of environmental factors, or to genetic factors other than those studied in this work.

ISSN:0960-314X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The selective serotonin reuptake inhibitor fluvoxamine is a very potent inhibitor of the liver enzyme CYP1A2, which is the major P450 catalysing the biotransformation of caffeine. Thus, a pharmacokinetic study was undertaken with the purpose of documenting a drug-drug interaction between fluvoxamine and caffeine.The study was carried out as a randomized, in vivo, cross-over study including eight healthy volunteers. In Period A of the study, each subject took 200 mg caffeine orally, and in Period B, the subjects took fluvoxamine 50 mg per day for 4 days and 100 mg per day for 8 days. On day 8 in Period B, the subjects again ingested 200 mg caffeine. After caffeine intake, blood and urine were sampled at regular intervals. Caffeine and its three primary demethylated metabolites, paraxanthine, theobromine and theophylline in plasma and the same four compounds plus 11 more metabolites in urine were assayed by HPLC.During fluvoxamine, the median of the total clearance of caffeine decreased from 107 ml min”1 to21mlmin~1 and the half-life increased from 5 to 31 h. The N3-demethylation clearance of caffeine to paraxanthine decreased from 46 to 9 ml min'1; the Nl- and N7-demethyIation clearances decreased from 21 to 9 ml min”1 and from 14 to 6 ml min”1, respectively.The results confirm that CYP1A2 is the main enzyme catalysing the biotransformation of caffeine, in particular the N3-demethylation and partly the Nl- and N7-demethyIation. The results indicate that intake of caffeine during fluvoxamine treatment may lead to caffeine intoxication. Finally, our study provides additional evidence that fluvoxamine can be used to probe CYP1A2 in drug metabolism.

ISSN:0960-314X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Pathological gambling has been termed both the 'pure' and the 'hidden' addiction. 'Pure' because it is not associated with the intake of any addicting substance, and 'hidden' because it is an extension of a common, socially accepted behaviour. The Taq Al variant of the human DRD2 gene has been associated with drug addiction, some forms of severe alcoholism, and other impulsive, addictive behaviours. We have sought to determine if there is a similar association with pathological gambling. A total of 222 non-Hispanic Caucasian pathological gamblers from multiple sites across the US participated in the study. Of these 171 donated a sample of blood, 127 filled out several questionnaires, and 102 did both. Of the 171 pathological gamblers 50.9% carried the D2Al allele versus 25.9% of the 714 known non-Hispanic Caucasian controls screened to exclude drug and alcohol abuse, p<0.00000001, odds ratio (OR)=2.96. For the 102 gamblers who filled out the questionnaires, 63.8% of those in the upper half of the Pathological Gambling Score (more severe) carried the D2A1 allele (OR versus controls=5.03), compared to 40.9% in the lower half (less severe). Of those who had no comorbid substance abuse, 44.1% carried the D2A1 allele, compared to 60.5% of those who had comorbid substance abuse. Forty-eight controls and 102 gamblers completed a shorter version of the Pathological Gambling Score. Of the 45 controls with a score of zero, 17.8% carried the D2A1 allele. Of the 99 gamblers with a score of 5 or more, 52.5% carried the D2A1 allele (X2=15.36, p=0.00009). These results suggest that genetic variants at the DRD2 gene play a role in pathological gambling, and support the concept that variants of this gene are a risk factor for impulsive and addictive behaviours.

ISSN:0960-314X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Chinese data on the polymorphic metabolism of debrisoquine, metoprolol, codeine and mephenytoin were collected and reanalysed using a meta-analysis method. There were no significant differences in the incidences of poor metabolizer (PM) between the separate series of debrisoquine, metoprolol and codeine, which are the three probe drugs reflecting the same enzyme polymorphism. PMs were detected at low frequencies for debrisoquine (1.20%; 95% confidence interval, CI: 0.67-1.98%), metoprolol (0.72%; CI: 0.29-1.49%) and codeine (0.48%, CI: 0.01-2.68%). The overall estimate of PM was 0.95% (CI: 0.60-1.42%) based on the 2427 determinations of all three probe drugs. The overall mean of PM of mephenytoin was 14.32% (12.26-16.38%) in the 1117 subjects. In summary, the present meta-analysis determined the accurate incidences of the genetic deficiency of S-mephenytoin 4'-hydroxy- Iase (cytochrome P450 2C19) and debrisoquine hydroxylase (cytochrome P450 2D6) in Chinese populations.

ISSN:0960-314X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

That CYP2D6 activity is an important determinant of nicotine metabolism and that people who have abnormal CYP2D6 genes are poor metabolizers of nicotine has been reported in the medical literature. The aim of this study was to assess the role of CYP2D6 in nicotine metabolism. Specifically, we compared the clearance of stable isotope-labelled nicotine and cotinine in 11 poor and 33 extensive metabolizers of dextromethorphan, a probe for CYP2D6 activity. The groups were matched by gender, age and ethnicity. Nicotine and cotinine kinetics were quite similar for cases and controls. These data suggest that CYP2D6 is not a major isozyme for the metabolism of nicotine or cotinine.

ISSN:0960-314X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Catechol-O-methyltransferase (COMT) inactivates catecholamines and catechol drugs such as L-DOPA. A common genetic polymorphism in humans is associated with a three-to-fourfold variation in COMT enzyme activity and is also associated with individual variation in COMT thermal instability. We now show that this is due to G—»A transition at codon 158 of the COMT gene that results in a valine to methionine substitution. The two alleles can be identified with a PCR-based restriction fragment length polymorphism analysis using the restriction enzyme Ma III. The identification of a gentic marker associated with significant alterations in enzyme activity will facilitate the analysis of a possible role for the COMT gene in neuropsychiatric conditions in which abnormalities in catecholamine neurotransmission are believed to occur, including mood disorders, schizophrenia, obsessive compulsive disorder, alcohol and substance abuse, and attention deficit hyperactivity disorder. In addition, this polymorphism may have pharmacogentic significance in that it will help make it possible to identify patients who display altered metabolism of catechol drugs.

ISSN:0960-314X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Glutathione transferases are involved in the detoxification of many zenobiotica involved in the etiology of cancer. To investigate the role of the glutathione S-transferase Ml deletion (GSTM1 *0/0) in bladder carcinogenesis, the polymerase chain reaction was used to determine the GSTMl genotypes of cancer patients (n=234) and hospital controls (n=202). Overall, the proportion of GSTMl*0/0 in the case group was 57%, compared to 50% in the control group giving an odds ratio (OR) of 1.33, (0.91-1.94; 95% confidence interval (CI)). Dividing the bladder cancer group into incident (n=87) and surviving case groups (n=147), a modest association between the GSTMl *0f0 genotype and bladder cancer was found in the surviving group, whereas, in the incident group no association was found. Logistic regression analysis of the incident cases, adjusting for age, gender, and cigarette smoking, revealed ORs of 1.12 (0.61-2.08) and 0.74 (0.33-1.73) for the malignant and benign tumours, respectively. The corresponding adjusted ORs for the surviving cases were 1.81 (1.04—3.13) for benign and 1.43 (0.80-2.56) for malignant tumours. Thus, in this study, the GSTMl deletion is not a risk factor for the development of bladder cancer, but may be related to the survival of the bladder cancer patients. This finding is very important for the design of case-control studies in general, and for the interpretation of existing data.

ISSN:0960-314X    

出版商:OVID    

年代:1996

数据来源: OVID

ISSN:0960-314X    

出版商:OVID    

年代:1996

数据来源: OVID

ISSN:0960-314X    

出版商:OVID    

年代:1996

数据来源: OVID