ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Genetic modulation of environmental exposures associated with common malignancies (lung and bladder) is an attractive mechanism to explain differential susceptibility to tobacco or occupation related carcinogens in the population. Epidemiologic studies to test the hypothesis of such associations and to evaluate evidence for a causal role for genetic factors in the etiology of chemically-induced tumors are challenging and require the close collaboration of epidemiologists, clinicians and laboratory investigators. In this work we review the evidence for an association of three polymorphisms of drug or xenobiotic metabolism with human cancers. Methodologic considerations and data relevant to evaluating a causal role for each polymorphism are considered. Fair to good support for both an association of the acetylation phenotype with occupationally-related bladder cancer and for an association of the debrisoquine metabolic phenotype and lung cancer is found, although in neither case is the evidence completely convincing. Epidemiologic evidence for the association of aryl hydrocarbon hydroxylase and lung cancer is presently problematic because of difficulties in the assay and subsequent confounding factors. DNA based assays are at various stages of development for each of the genotypes and promise to simplify future studies while introducing new methodologic pitfalls. Further studies in all three areas are warranted as each has important implications for the understanding of the carcinogenic process, etiology and the public health aspects of common malignancies.

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

In this study of 221 lung cancer patients and 212 controls, no association between aMspI polymorphism in theCYP1A1gene and an increased risk of lung cancer was found. Histological type, smoking habits and family history were also examined. No associations between theMspI restriction fragment length polymorphism in theCYP1A1gene and any of these parameters were found. These results are in contrast to a previous report by a Japanese group (Kawajiriet al.,1990) who found an association between the less common allele and an increased susceptibility to lung cancer in their population. The frequency of the less commonMspI 1.9 kb fragment allele (C2) appears to be three times greater in the Japanese population than in the Norwegian population and a Caucasian population of North America. It is possible that in the Asian population thisMspI polymorphism is in linkage disequilibrium with another mutation important forCYP1A1gene expression, whereas in the Caucasian population these mutations are in equilibrium

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

A variantCYP2D6(C)P450 protein was found in a liver characterized by deficient microsomal metabolism of bufuralol and sparteine, prototypical substrates for the debrisoquine-sparteine drug oxidation polymorphism. This protein was present at decreased levels in liver and had a slightly different relative mobility on SDS-polyacrylamide gels. The cDNA cloning and sequencing of the variant, designatedCYP2D6(C), revealed that its mRNA lacked a single codon resulting in deletion of Lys281. This was the result of a three base pair deletion at the 3' end ofCYP2D6exon 5. TheCYP2D6(C)P450, produced in HepG2 cells using vaccinia virus mediated cDNA expression displayed Km values toward bufuralol, debrisoquine and sparteine that were not significantly different from wild typeCYP2D6. These data suggest that the poor metabolizer phenotype in livers expressingCYP2D6(C)is not due to a catalytically defective enzyme but perhaps due to decreased levels of the P450 protein in microsomal membranes. Low microsomalCYP2D6(C)contents could result from deficient membrane insertion or decreased stability of the P450 protein. A polymerase chain reaction-based procedure, developed to detectCYP2D6(C)alleles, indicates that this variant probably represents less than 1.5% of allCYP2D6alleles.

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

A randomly selected population of 73 volunteers, together with 22 previously established poor metabolisers of debrisoquine, were phenotyped for their ability to 4-hydroxylate debrisoquine and were also analysed for a number of mutations in theCYP2D6gene. Genotyping was performed using both restriction fragment length polymorphism with the restriction enzyme Xbα I, together with two separate polymerase chain reaction assays. Together, these assays detected 98% of mutant alleles in the poor metaboliser group which corresponded to positive identification of 95% of this group. The most common mutant allele detected as the 29B which comprised 75% of total alleles in the poor metaboliser group, whereas the 29A had a frequency of 0.11. Two other allelic variants, which were detectable by restriction fragment length polymorphism analysis occurred at frequencies of 0.07 and 0.05. In the volunteer group, 2.7% of subjects were genotypically poor metabolisers, 35.6% heterozygous extensive metabolisers and 61.7% homozygous extensive metabolisers, on the basis of the genotyping assays used. A good correlation between debrisoquine metabolic ratio and genotype was obtained particularly for subjects genotyped as homozygous extensive metabolisers.

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Mephenytoin is the prototype substrate for the genetically regulated, polymorphically distributed cytochrome P450, mephenytoin hydroxylase. Mephenytoin is an anticonvulsant which has been associated with leukopenia when used chronically. The haematologic effects of a single dose of oral mephenytoin, as is typically used to determine drug metabolism phenotype for this polymorphism, have not been reported. We administered 100 mg oral racemic mephenytoin to 30 healthy male volunteers and measured complete blood count three times weekly for 23 days. The time dependency of the urinary ratio of S to R mephenytoin in five serial urine samples (0-4, 4-8, 8-16, 16-24 and 24-32 h after the dose) was evaluated. There were no significant decreases from baseline in any subject in leukocyte count, haematocrit or platelet count. Two of the 30 subjects both of Indian extraction, were poor metabolizers of mephenytoin. The S:R ratio decreased with time (p= 0.001). Using the 0-4 h urine, one subject would have been misphenotyped as a poor metabolizer; phenotype assignments were in agreement with each other based on all subsequent urine collections. We conclude that there is no evidence that single dose mephenytoin is associated with haematologic toxicity in healthy male volunteers, and that the 4-8 h post-dose urine is as reliable as the 24-32 h collection for assignment of phenotype.

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

The inheritance of rat liver N-acetyltransferase polymorphism was investigated with reciprocal genetic crosses between slow (NSD/N) and rapid (Peth/N) acetylator strains. Rat liver N-acetyltransferase activity was determined using a pectrophotometric assay which measured the amount of arylamine substrate present after incubation with N-acetyltransferase in vitro. Male N-acetyltransferase activities assayed in liver preparations using p-aminobenzoic acid and p-toluidine as substrates indicate bimodality of the parental strains and unimodality of the F-l generation; limited data suggest trimodality (not significantly different from a 1:2:1 ratio) of the F-2 generation. Reciprocal crosses of WKY/N, another slow acetylator strain, and the Peth/N strain gave results similar to those of the NSD/N x Peth/N cross. Female N-acetyltransferase activities in all strains studied were lower than male N-acetyltransferase activities, but were similarly distributed in the parental and F-l generations. The male/female N-acetyltransferase activity ratio was substrate- and genotype-dependent. Results show that regulation of the variation of rat liver N-acetyltransferase activity is consistent with autosomal Mendelian inheritance of two major alleles at a single gene locus.

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Human serum paraoxonase is a polymorphic enzyme that is capable of catalyzing the hydrolysis of paraoxon and other organophosphates, some carbamates and certain aromatic carboxylic acid esters. This enzyme is specified by two allelic genes at one autosomal locus (isozymes ‘A’ and ‘B’). The purpose of this study was to examine the paraoxonase activity of 105 Turkish subjects. Paraoxonase activities ranged from 39.6 to 278.2 nmol p-nitrophenol formed per ml of serum per min. Paraoxonase phenotypes could be clearly identified by salt and paraoxonase:arylesterase activity ratio characteristics. The gene frequencies were 0.632 for the low activity allele (A) and 0.368 for the high activity allele (B).

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID