ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The pharmacogenetic differences among individuals in their capacity to metabolize ingested alcohol are possibly responsible for the large inter-individual and inter-ethnic variations observed in the outcome of alcohol use and misuse. Based on results of adoption, twin, and family studies it is now widely accepted that the vulnerability to alcoholism is determined by genetic factors as well as by environment. There is a constant search for biological markers and specific genes which could identify individuals genetically predisposed to alcohol abuse and alcoholism. Numerous ‘candidate genes’ for alcoholism have been suggested including the alcohol metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH).Both ADH and ALDH exhibit genetic heterogeneity. An atypical form of ADH (ADH2), which contains a variant β2subunit instead of the usual β1subunit, differs substantially from the usual form in its kinetic properties and is found more frequently among the Japanese, Chinese and other Mongoloid populations than in Caucasoids and Negroids. A widely prevalent genetic polymorphism has been observed for ALDH; about 50% of Japanese and Chinese livers possess an inactive ALDH (ALDH2isozyme) whereas none of the Caucasian or Negroid populations show this isozyme abnormality.These metabolic polymorphisms seem to contribute to differences in the invivoelimination rate of ethanol and acetaldehyde, and may explain differences in alcohol-related behaviour and its disease outcome. Taken together, Orientals who possess an atypicalALDH2gene are more sensitive to acute responses to alcohol, tend to be discouraged from drinking alcohol, and consequently are at lower risk of developing alcohol-related disorders. However, more work is needed to support these findings. Recent advances in molecular genetics have made it possible to analyse directly the human genome. This may help in a better understanding of the complex genetic and environmental factors in alcohol abuse by providing prospects for identification of gene loci which may be responsible for predisposition to, and protection from, alcoholism.

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Expression of the three major cytosolic classes of glutathioneS-transferases (GST; Pi, Alpha and Mu) was examined by 21) gel analysis and Western blotting of biopsies from 26 patients diagnosed with ovarian carcinoma. In contrast to other tissues, at least one ‘constitutive’ subunit from each of the three major cytosolic GST classes was expressed. In most cases, pi appeared to be the major form present, although levels of alpha and mu subunit expression were approximately equal to pi in some patients. There was no detectable effect of prior chemotherapy on enzyme activity. Mean transferase activity for primary carcinoma was 79.9 ± 11.9 (mean ± SEM; nmol min-1mg-1), with three pair-matched normal tissues showing minor decreases in transferase activity. One sample, in which a 32% increase in tumour enzyme activity was noted, was from a patient with primary disease and was associated with marked overexpression of a relatively basic form of alpha which was absent from the matching normal tissue, but present in 20% of all tumours examined. RFLP analysis of genomic tumour DNA using a human mu class cDNA probe indicated that at least two of the three mu forms (the ‘constitutive’ form and one other) observed in ovarian tissue were allelic variants, as a one-to-one correlation was observed between the presence of twoHindIII fragments at 13.1 and 2.2 kb and expression of a second, more basic, variable form. This latter form was positively identified as the mu class subunit μ based on Southern analysis and was seen to be present in 40% of the samples examined. However, in the absence of μ expression, at least one other mu class subunit probably corresponding to GST ψ was seen to be present. Thus, at least in ovarian tissues, absence of the μ subunit does not necessarily imply a lack of ability to metabolize μ substrates, as ψ has similar catalytic activity. A third mu subunit, probably corresponding to GST &phis; based on its relatively acidic pi, was also noted in 72% of samples examined, but has unknown substrate specificity. Increased expression of both alpha and mu forms may be of relevance to disease diagnosis and drug response.

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Six human cytochrome P450s expressed in HepG2 cells using vaccinia virus cDNA-directed expression, were used to study the biotransformation of caffeine and its metabolites. CYP1A2 alone was responsible for caffeine 3-demethylation and paraxanthine 7-demethylation; in addition, 1A2 catalysed virtually all reactions related to caffeine and its metabolites. The metabolic profile of caffeine biotransformation by CYP1A2 averaged 81.5% for paraxanthine, 10.8% for theobromine and 5.4% for theophylline formation. It remained quite uniform when caffeine concentrations were varied. The most striking finding was that CYP2E1 (the ethanol-inducible form) had major influences upon caffeine metabolism: in particular, it catalysed the formation of theophylline and theobromine from caffeine. Thus, the in vivo metabolite profiling of caffeine may reveal CYP2E1 activities in addition to the previously documented activities of CYP1A2, polymorphic N-acetyltransferase and xanthine oxidase.

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

We describe a method of detecting human DNA mutations with nonradioactive, biotinylated allele-specific oligonucleotide probes. This method can detect seven different mutations in the butyrylcholinesterase. cystic fibrosis, andN-acetyltransferase genes under identical assay conditions. This indicates that it may be used to detect mutations responsible for a wide variety of genetic diseases and pharmacogenetic conditions. The method involves first amplifying selected DNA fragments by the polymerase chain reaction and dot blotting the amplified DNA in duplicate onto small nitrocellulose squares. Each dot blot is then hybridized in individual wells containing a tetramethylammonium chloride solution with short biotinylated probes specific for either the normal or mutant allele. Successfully hybridized probes are detected by a simple colorimetric reaction using an avidin-alkaline phosphatase conjugate, which yields a very strong, clear signal. DNA from homozygous normal or mutant individuals hybridizes only to the normal- or mutant-specific probes respectively, while DNA from heterozygous individuals hybridizes equally well with both probes. These results can be easily interpreted to assign a genotype to the sample DNA. This method is amenable to automation, and may be useful in clinical laboratories for diagnosis of a wide variety of DNA mutations responsible for unusual reactions to drugs and environmental chemicals.

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The 0–8 hour urinary distributions of the metabolic ratios of sparteine (100 mg), debrisoquine (10 mg) and metoprolol (100 mg) were measured in 165 healthy, unrelated, black Nigerian medical students. There was a weak correlation (rs= 0.51,p< 0.001];n= 82) between the metoproiol/α-hydroxymetoprolol (M/HM) and the sparteine/total (2-) dehydrosparteine (S/DHS) ratios. No significant correlations were found between the debrisoquine/4-hydroxydebrisoquine (D/HD) and M/HM ratios (rs= 0.16, (n= 33) and between the D/HD and S/DHS ratios (rs= 0.31,n= 38). Both visual inspection and kernel density analysis of the data suggested the presence of two phenotypic groups for sparteine oxidation, with 4+ACU- of the population studied being putative poor metabolizers. In contrast bimodality was not apparent in the distribution of the log10M/HM and log10D/HD ratios. These findings provide evidence for a dissociation in the control of metoprolol, sparteine and debrisoquine oxidation in Nigerians and highlight the difficulties in the interpretation of data from pharmacogenetic studies in different ethnic groups.

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID