ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

In vitropharmacological responses of fresh biopsy specimens of human skeletal muscle were used as indicators of some intrinsic muscle properties. The measured parameters that were utilized for the current study were contractures inducedin vitroby caffeine or by caffeine plus halothane. The opportunity to study such specimens arose from clinical testing for diagnosing the genetic predisposition to malignant hyperthermia, a potentially fatal complication of anaesthesia. The current analysis covers data from over 1000 subjects, most of whom were clinical suspects and relatives of these. Responsiveness of the muscle specimens varied over two orders of magnitude. The frequency distribution curves suggest that the variation does not represent a continuum but that there are three or more clusters of functional variants. Muscle specimens from males were on average more responsive to caffeine than were those from females. Correlations within father-son and brother-brother pairs indicated complete heritability of responsiveness; this might have been expected but the surprise was a lack of correlation within mother-daughter pairs. There was an intermediate correlation in father-daughter pairs. The sex difference in heritability could be due to gender-related modifying genes or due to secondary modification of the muscle response in females by sex-related, perhaps hormonal factors. Among the effects of age appeared to be poor development in early childhood of the potentiation of the caffeine contracture by halothane.

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Debrisoquine-hydroxylase (P450 2D6)‡ phenotype was determined in 116 individuals using dextromethorphan as the substrate probe. Polymerase chain reaction and restriction fragment length polymorphism analyses were used to detect inactivating mutations in the CYP2D6 gene and assign genotype in all 116 individuals. Using a urinary metabolic ratio (DM/DT) of ≥0.3 to define poor metabolizer (PM) phenotypes, 96 subjects were extensive metabolizers (EM) and 20 were PMs. The CYP2D6(B) mutation was the most common mutation, present in 18% of phenotypic EM alleles and 66% of the alleles in PM phenotypes. The CYP2D6(A) mutation (8% of PM alleles) and the CYP2D6 gene deletion (2.6% of PM alleles) were found less frequently. Seven different variants of the CYP2D6 gene were found. In subjects with two mutant alleles, genotype correctly predicted the PM phenotype in 100% (n = 13). Overall, genotype agreed with phenotype assignments in 109 of 116 (94%) subjects. Seven subjects with a wild-type allele at the CYP2D6(A) and CYP2D6(B) loci were phenotypic PMs, representing the only discrepant results. These discrepancies could be due to the imprecision of phenotype assignment or to as yet unknown mutations in CYP2D6. Although the median urinary metabolic ratio was significantly lower in homozygous EMs compared with heterozygous EMs, there was extensive overlap in metabolic ratios in these two groups, indicating that the DM/DT metabolic ratio cannot reliably discriminate homozygous EMs from heterozygous EMs.

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

A determination of the mechanisms of drug resistance in tumour cells is important for developing strategies to combat such resistance in persons receiving chemotherapy. This report describes a combined cellular, biochemical, and molecular analysis of a dog kidney cell line selected for resistance to increasing levels of the hydrophilic antifolate, aminopterin. Three distinct drug resistance phenotypes were observed in cells exhibiting high levels of aminopterin resistance. Two of these phenotypes were decreased aminopterin accumulation and increased levels of dihydrofolate reductase specific activity. The third drug resistance phenotype was noted initially as cross resistance to a variety of hydrophobic drugs indicating multidrug resistance. Bioc.hemical assays demonstrated reduced accumulation of the hydrophobic fluorescent drug daunorubicin and of3H-colchicine in the aminopterin resistant cells. These results were then correlated with increased levels of the multidrug resistance (mdr) gene product, P-glycoprotein, and mdr mRNA levels in the aminopterin resistant cells. However, experiments designed to prove a role for expression of the mdr gene in providing a degree of aminopterin resistance were unsuccessful. It is concluded that aminopterin selection in these dog kidney cells resulted in expression of at least three distinct drug resistance phenotypes and that one of these phenotypes, multidrug resistance, represented a secondary response to the aminopterin selection.

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

The relationship between genotypes associated with restriction fragment length polymorphisms at the P450 CYP2D locus and the metabolic phenotypes for sparteine in healthy Japanese subjects was investigated. Four distinct restriction fragments of 44 kb, 29 kb, 11.5 kb or 16 + 9 kb after digestion with Xba I were observed. The genotype of Xba I 11.5 kb, which is predictive of the poor metabolizer phenotype in Caucasians is also associated with Japanese poor metabolizers. Most Xba I 44 kb are associated with the extensive metabolizer phenotype. However, one Xba I 44 kb haplotype in linkage disequilibrium with a Bam HI restriction fragment length polymorphism allele, designated Bam HI 2.3 kb-, appears to be a novel mutant CYP2D6 allele in Japanese subjects having the poor metabolizer phenotype.

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

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