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Biomedical subjects

L Bathum

Publications and source records attributed to L Bathum.

30 records · Page 2Linked to original sources
PubMed1999

CYP2D6 polymorphism in systemic lupus erythematosus patients.

OBJECTIVES: To determine whether patients with idiopathic systemic lupus erythematosus (SLE) are associated with impaired CYP2D6 activity and to gain insight into whether there is an association between particular CYP2D6 genotypes and susceptibility to SLE, and whether CYP2D6 polymorphism is linked to any specific clinical features of SLE. METHODS: Debrisoquine sulfate (10 mg p.o.) was given to 159 healthy volunteers and 39 idiopathic SLE patients. Genotypic assay was carried out in 80 healthy volunteers and 32 patients. A 10-ml blood sample was drawn for genotypic assay. Debrisoquine and 4-hydroxydebrisoquine were determined in 8-h urine samples. Blood samples were analysed for the presence of mutations in the CYP2D6 gene, by using polymerase chain reaction (PCR) specific for CYP2D6*3 and CYP2D6*4 alleles. RESULTS: The metabolic ratio of debrisoquine to 4-hydroxydebrisoquine ranged from 0.01 to 86.98 in healthy subjects and from 0.02 to 96 in SLE patients. We observed the poor metabolizer(PM) debrisoquine phenotype in three of 39 patients with idiopathic SLE (7.6%) and five of 159 healthy subjects (3.1%). There was no significant difference in the frequency of PM phenotypes between idiopathic SLE and healthy subjects (Fisher's exact test, P = 0.19). No significant difference in the distribution of overall genotypes and allele frequencies were observed between the two groups. No significant relationships were found between specific clinical features and the overall genotype. CONCLUSION: The results of this study confirm that CYP2D6 activity is not impaired in SLE and that there is no association between SLE and phenotypic CYP2D6 status. The results also showed that there was no difference in the frequency of CYP2D6A and CYP2D6B alleles between controls and patients with SLE.

Adult↗
PubMed1999

Phenotypes and genotypes for CYP2D6 and CYP2C19 in a black Tanzanian population.

AIMS: CYP2D6 and CYP2C19 are polymorphically expressed enzymes that show marked interindividual and interethnic variation. The aim of this study was to determine the frequency of the defective alleles in CYP2D6 and CYP2C19 in Africans and to test whether the genotype for CYP2C19 is better correlated with the proguanil/cylcoguanil ratio than the mephenytoin S/R ratio. METHODS: Two hundred and sixteen black Tanzanians were phenotyped for CYP2D6 with the use of sparteine, and for CYP2C19 with the use of mephenytoin and proguanil. Of these 196 subjects were also genotyped for CYP2D6 (including the CYP2D6*1, CYP2D6*3 and CYP2D6*4 alleles) and 195 were genotyped for CYP2C19 (including the CYP2C19*1, CYP2C19*2 and the CYP2C19*3 alleles). Furthermore 100 subjects were examined for the allele duplication in CYP2D6, leading to ultrarapid metabolism, with long PCR. RESULTS: The sparteine metabolic ratio (MR) was statistically significantly higher in the Tanzanian group of homozygous, extensive metabolizers compared to a historical control group of white Danish extensive metabolizers. Only one poor metabolizer for CYP2D6 (MR=124 and genotype CYP2D6*1/CYP2D6*4 ) was found. The gene frequencies were 0.96 for the CYP2D6*1 allele and 0.04 for the CYP2D6*4 allele. No CYP2D6*3 alleles were found. Nine subjects had an allele duplication in CYP2D6 (9%). For CYP2C19 there were seven subjects (3. 6%) who were phenotyped as poor metabolizers, but only three subjects (1.5%) had a genotype (CYP2C19*2/CYP2C19*2 ) indicative of poor metabolism. The gene frequencies were 0.90 for the CYP2C19*1 allele and 0.10 for the CYP2C19*2 allele. No CYP2C19*3 alleles were found. The mephenytoin S/R ratios were not bimodally distributed. CONCLUSIONS: Both the genotyping and phenotyping results show that there is a substantial difference between an African black population and a Caucasian population in the capacity to metabolize drugs via CYP2D6 and CYP2C19.

Adult↗
PubMed1999

CYP2C19 genotype does not represent a genetic predisposition in idiopathic systemic lupus erythematosus.

BACKGROUND: The aetiology of systemic lupus erythematosus (SLE) is still unknown. In several cases, however, chemicals or drugs were identified as aetiological agents and associations with certain phenotypes of drug metabolising enzymes have been reported. The purpose of this study was to discover if there is an association between CYP2C19 polymorphism and susceptibility to SLE. METHODS: Racemic mephenytoin (100 mg orally) was given to healthy volunteers (n = 161) and SLE patients (n = 37) and then S-mephenytoin and R-mephenytoin were determined in eight hour urine samples. A 10 ml blood sample was obtained from healthy volunteers (n = 80) and SLE patients (n = 69) for genotypic assay. Each blood sample was tested for the detection of CYP2C19*1 and CYP2C19*2 (formerly wt and m1 respectively) by oligonucleotide ligation assay. RESULTS: The ratio of S/R-mephenytoin ranged from < 0.1 to 1.293 in healthy subjects and from < 0.1 to 1.067 in SLE patients. PM phenotype was observed in 2 of 37 patients with idiopathic SLE (5.4%) and 6 of 161 healthy subjects (3.7%). There were no significant differences in the frequency of PM phenotypes between the groups (Fisher's exact test, p = 0.64) or in the frequency distribution profiles of ratios of S-mephenytoin to R-mephenytoin. No significant differences in distribution of overall genotypes and in allele frequencies were observed between the two groups. No significant relation was found between clinical features and the overall genotype. CONCLUSION: The results of this study indicate that CYP2C19 genotype does not represent a genetic predisposition in idiopathic SLE patients.

Adult↗
PubMed1998

Genotypes for the cytochrome P450 enzymes CYP2D6 and CYP2C19 in human longevitY. Role of CYP2D6 and CYP2C19 in longevity.

OBJECTIVE: To test whether some genotypes for CYP2D6 or CYP2C19 could contribute to longevity, we genotyped 241 Danish nonagenarians and centenarians for CYP2D6 and CYP2C19. METHODS: For CYP2D6 we identified the alleles CYP2D6*1, CYP2D6*3 and CYP2D6*4 with allele-specific polymerase chain reaction (PCR). The CYP2D6*5 alleles were identified with a long PCR method. For CYP2C19 we identified the alleles CYP2C19*1, CYP2C19*2 and CYP2C19*3 with an oligonucleotide ligation assay. RESULTS: The four alleles for CYP2D6 did not occur in Hardy-Weinberg proportions. The frequency of poor metabolism was slightly higher (10.2%) than expected [7.7%; odds ratio (OR) = 1.36 (0.75-2.40)]. The genotypes for CYP2C19 occur in Hardy-Weinberg proportions. The frequency of poor metabolism (3.8%) was not significantly different from a young control group [3.1%; OR = 1.21 (0.26-5.75)]. CONCLUSION: CYP2D6 could play a role in human longevity due to the lack of Hardy-Weinberg proportions. If CYP2D6 only plays a role in longevity by protecting the poor metabolizers from cancer, we should expect a rise in the frequency in these genotypes in Denmark from 7.7% among young adults to 10-11% among very old people. We found a frequency of poor metabolism of 10.2% in the very old group. CYP2C19 is - due to the occurrence of Hardy-Weinberg proportions and the expected number of poor metabolizers unlikely to contribute to human longevity.

Adult↗
PubMed1998

A dual label oligonucleotide ligation assay for detection of the CYP2C19*1, CYP2C19*2, and CYP2C19*3 alleles involving time-resolved fluorometry.

CYP2C19 (S-mephenytoin hydroxylase) is a polymorphically expressed enzyme. Currently, two defective alleles are known--CYP2C19*2 and CYP2C19*3. The authors have developed an oligonucleotide ligation assay to detect these two alleles. This assay combines the hybridization of one common, biotinylated capture probe and two allele-specific probes to the target DNA, with the ability of a DNA ligase to distinguish mismatched nucleotides. The probes are only ligated if they are base paired correctly to the target strand. The biotin is bound to streptavidin, and all DNA not covalently bound to the biotin-labeled capture probe, is removed in a washing procedure. The allele-specific probes are labeled with either europium or samarium, and their emission can be measured simultaneously. The ratio between the emission separates the genotypes. This method was applied on DNA from 19 whites and 21 Vietnamese living in Denmark. All genotypes determined by the assay were consistent with the results from restriction enzyme cleavage. There were 12 poor metabolizers; 10 homozygous CYP2C19*2/CYP2C19*2, one heterozygous CYP2C19*2/CYP2C19*3, and one heterozygous CYP2C19*1/CYP2C19*2. The authors conclude that this assay is well-suited for a high throughput of samples in a routine laboratory. The finding of an apparently heterozygous CYP2C19*1/CYP2C19*2 poor metabolizer, confirms that there are still unknown mutations in CYP2C19.

Alleles↗
PubMed1998

Ultrarapid metabolism of sparteine: frequency of alleles with duplicated CYP2D6 genes in a Danish population as determined by restriction fragment length polymorphism and long polymerase chain reaction.

CYP2D6 is a polymorphically expressed enzyme with two phenotypes. Poor metabolizers lack the enzyme caused by inactivating mutations in the CYP2D6 gene and extensive metabolizers have at least one active CYP2D6 gene. Extensive metabolizers with very high capacity for CYP2D6 dependent drug metabolisms are termed ultrarapid metabolizers and carry alleles with duplicated, multi duplicated or amplified CYP2D6 genes. In the present study, we examined the frequency of CYP2D6 gene duplications in a Danish population and validated a long polymerase chain reaction method for identification of ultrarapid metabolizers. Sixty individuals having a metabolic ratio for sparteine at or below 0.15 were selected and a control group of 53 individuals with a metabolic ratio between 0.16 and 12.4 was used. Based on EcoRI restriction fragment length polymorphism analysis, eight individuals were found with a duplicated CYP2D6 gene, whereas using a long polymerase chain reaction method, nine individuals with a 3.6 kb fragment indicative of two CYP2D6 genes in tandem were found among the 60 individuals with a low metabolic ratio. No gene duplication was found in the control group or in any individuals with a metabolic ratio > 0.14. Based on these results, we estimate the frequency of individuals with CYP2D6 duplication in the Danish population to be 0.8%, which is comparable to the frequency in the Swedish and the German populations, but considerably lower than in Spanish or African populations. We conclude that the long polymerase chain reaction assay is simple and reliable for detection of duplications of the CYP2D6 gene.

Alleles↗
PubMed1995

[Carbohydrate deficient transferrin--a reliable marker of alcohol abuse?].

Carbohydrate deficient transferrin (CDT) is an isoform of transferrin with a reduced carbohydrate content, especially the negatively charged sialic acid. This alters the pI value and allows the separation of CDT from normal transferrin. CDT has a higher sensitivity and specificity than other currently known markers of alcoholism. Increased CDT values are found in patients with non-alcoholic liver disease. The cost of the analysis is high and the benefit of this marker is still uncertain.

Alcoholism↗
PubMed1994

[Percutaneous endoscopic gastrostomy].

Tube feeding is commonly used in providing enteral nutrition to the patient with dysphagia. The percutaneous endoscopic gastrostomy (PEG) is an alternative to the nasogastric tube (NG) and the surgical gastrostomy. The advantages of PEG are short procedure time, the avoidance of using an operating theatre and general anaesthesia and reduced cost. The main indication for PEG is dysphagia due to neurological disease and cancer in the pharynx and oesophagus. A gastrostomy is cosmetically more acceptable than NG, self extubation is more difficult for the confused patient, tube diameter is larger and therefore the tube is not so easily blocked. The patient with a gastrostomy tube is more mobile and is able to start oral nutrition at the same time as receiving enteral nutrition through the gastrostomy tube.

Aged↗
PubMed1989

Mephenytoin and sparteine oxidation: genetic polymorphisms in Denmark.

The oxidation of mephenytoin was polymorphic in 358 healthy Danish volunteers. The ratio between the chromatographic peak areas of (S)- and (R)-mephenytoin (S/R) in 12 h urine was less than or equal to 0.48 in 349 extensive metabolizers (EM) and greater than or equal to 1 in 9 (2.5%) poor metabolizers (PM). Concomitant intake of mephenytoin and sparteine and subsequent assay by gas chromatography had no influence on the test results (mephenytoin S/R ratio or sparteine metabolic ratio). Among ten parents and seven siblings to six unrelated PM of mephenytoin only one (1/17 = 5.9%) was a PM. The pedigrees were compatible with an autosomal recessive mode of inheritance.

Adolescent↗