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Biomedical subjects

J R Idle

Publications and source records attributed to J R Idle.

At least 73 records · Page 4Linked to original sources
PubMed1994

Reduced serum lipoprotein(a) levels in patients with primary biliary cirrhosis.

Lipoprotein(a) (Lp(a)) is a unique lipoprotein, elevated serum levels of which are independently associated with an increased risk of coronary heart disease (CHD). Primary biliary cirrhosis (PBC) is often associated with high serum cholesterol, itself a risk factor for CHD. Despite this, patients with PBC are thought to have a lower than expected incidence of CHD. We hypothesised that this may be related to low serum levels of Lp(a) in PBC patients. This was investigated by collecting fasting blood samples from 42 patients with PBC, 39 age- and sex-matched subjects with non-PBC liver disease and 432 community control subjects. Serum was analysed for total cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol and apolipoproteins A1 and B (apo A1 and apo B). Lp(a) was measured by an enzyme-linked immunosorbent assay (ELISA) technique. There was a significant reduction of Lp(a) concentrations in the PBC group compared with the healthy controls (median value 28.5 mg/l vs. 75.0 mg/l, P < 0.005) and between the non-PBC liver disease group (median value 52.0 mg/l) and control group (P = 0.001). Within both the liver disease and PBC patient groups there were significant negative correlations between Lp(a) levels and bilirubin (R = -0.564, P < 0.001 and R = -0.395, P = 0.010 respectively). This preliminary study has demonstrated reduced Lp(a) levels in PBC patients which may be a contributory factor to explain a possible cardioprotective effect in such patients, despite elevated LDL cholesterol levels.

Bilirubin↗
PubMed1994

The cytochrome P450 CYP2D6 allelic variant CYP2D6J and related polymorphisms in a European population.

DNA from two subjects showing anomalous CYP2D6 phenotype-genotype relationships was analysed for the presence of new CYP2D6 mutations by single strand conformational polymorphism (SSCP) analysis. One of these subjects was homozygous for polymorphisms in exon 1 and exon 9 previously detected in Oriental populations and termed the CYP2D6J allele. The frequency of these polymorphisms and their effect on phenotype was investigated in a European population with a small Chinese population as a control group. Subjects homozygous for both polymorphisms showed impaired metabolism of debrisoquine whereas subjects with the exon 9 mutation only appeared to show similar metabolism to the wild-type. The CYP2D6J allele frequency was 0.05 in the European group compared with 0.47 for the Chinese group. The relationship between the CYP2D6J allele and the exon 9 polymorphism and the presence of insertions upstream of CYP2D6 detectable by RFLP analysis with Xba I was investigated. In the Chinese group the insertion appeared to be associated with the CYP2D6J allele but in the European group no association was detected. Subjects homozygous for the CYP2D6J allele appear to show a similar debrisoquine phenotype to those heterozygous for CYP2D6-inactivating mutations but the exon 9 polymorphism or the presence of an upstream insertion without an associated CYP2D6B or CYP2D6J allele does not appear to affect enzyme activity.

Alleles↗
PubMed1994

Amlodipine-induced gingival overgrowth.

Amlodipine is a calcium channel blocker used in the management of angina and hypertension. We report 3 cases of gingival overgrowth in adult dentate patients associated with chronic usage of this drug. Gingival changes occurred within 3 months of dosage and appeared to be compounded by the patient's existing periodontal condition. In all 3 patients, there was sequestration of amlodipine in their crevicular fluid. The significance of this finding in relation to the pathogenesis of this unwanted effect remains to be elucidated.

Adult↗
PubMed1994

Genotyping for polymorphisms in xenobiotic metabolism as a predictor of disease susceptibility.

Polymorphisms in many xenobiotic metabolizing enzymes occur leading to variation in the level of enzyme expression in vivo. Enzymes showing such polymorphisms include the cytochrome P450 enzymes CYP1A1, CYP1A2, CYP2A6, CYP2D6, and CYP2E1 and the phase two metabolism enzymes glutathione S-transferase MI (GSTMI) and arylamine N-acetyltransferase 2 (NAT2). In the past, these polymorphisms have been studied by phenotyping using in vivo administration of probe drugs. However, the mutations which give rise to several of these polymorphisms have now been identified and genotyping assays for polymorphisms in CYP1A1, CYP2A6, CYP2D6, CYP2E1, GSTMI, and NAT2 have been developed. Specific phenotypes for several of the polymorphic enzymes have been associated with increased susceptibility to malignancy, particularly lung and bladder cancer, and Parkinson's disease. These associations are likely to be due to altered activation or detoxication of chemicals initiating these diseases, including components of tobacco smoke and neurotoxins. The substrate specificity and tissue distribution of polymorphic enzymes implicated in disease causation discussed with particular reference to previously described disease-phenotype associations.

Animals↗
PubMed1994

Pharmacogenetic phenotyping and genotyping. Present status and future potential.

Enzymes that metabolise foreign compounds exhibit a large degree of interindividual variability in their levels of expression. In a number of instances this variability can be accounted for by null or variant alleles resulting from mutations in genes encoding these enzymes. Human variability in drug metabolism can be determined by biochemical and pharmacological assays. In cases where a genetic change has been characterised, polymerase chain reaction techniques have been developed to diagnose metabolism deficiencies. Genetic differences in certain foreign compound metabolising enzymes such as glutathione S-transferase M1, N-acetyltransferase 2 and CYP2D6 have been shown to be associated with risk for developing environmentally and occupationally based diseases such as cancer. Drug therapy can also be compromised by the existence of genetic deficiencies in a number of enzymes, including CYP2D6. It is anticipated that determination of an individual's drug metabolism capabilities by use of phenotyping and genotyping tests will allow for more rational and safe drug administration protocols.

Biotransformation↗
PubMed1994

Phenotype/genotype relationships for the cytochrome P450 enzyme CYP2D6 in rheumatoid arthritis: influence of drug therapy and disease activity.

OBJECTIVE: To determine whether particular genotypes for the cytochrome P450 enzyme CYP2D6, a polymorphic enzyme, are associated with susceptibility to rheumatoid arthritis (RA) and whether CYP2D6 enzyme activity is altered as a result of the disease or its treatment. METHODS: CYP2D6 genotypes and metabolic phenotypes were determined for 53 patients with RA and 73 healthy controls. Genotyping was carried out by restriction fragment length polymorphism analysis with the restriction enzyme XbaI and by 2 separate polymerase chain reaction assays; phenotyping was by analysis of in vivo metabolism of the probe drug debrisoquin. RESULTS: No significant difference in the distribution of overall genotypes between the 2 groups was observed. When the frequency of individual alleles was investigated, a significant difference in allele frequency for the CYP2D6D allele (p < 0.005) was observed with fewer patients with RA showing this mutation. Metabolic phenotypes were broadly similar between the patients and controls. However, a number of the patients with RA showed higher than expected metabolic ratios for their particular genotype due to interference by the analgesic dextropropoxyphene in the phenotyping procedure. CONCLUSION: Our findings demonstrate that CYP2D6 activity is not impaired in RA.

Adult↗
PubMed1994

Genotyping of the CYP2D6 gene in Norwegian lung cancer patients and controls.

Genotyping of five CYP2D6 alleles (wt, A,B,D,E) has been performed in 218 lung cancer patients and 289 healthy controls. PCR-methods were used to determine the CYP2D6A and CYP2D6B alleles. Both patients and controls were of Caucasian Norwegian origin. In the lung cancer group all major histological types were represented. The frequency of the CYP2D6B allele which is associated with poor metabolizers (PM), was 0.235 in the lung cancer population and 0.200 in the control population. The frequencies of the CYP2D6A allele, another mutant allele associated with the PM-phenotype, were 0.007 and 0.013 in the lung cancer and control population respectively. RFLP analysis using the restriction enzyme Xba I to determine the D and E alleles, was also performed on 178 of the patients and on 118 of the controls. The frequency of the deletion variant CYP2D6D (13 kb) was 0.025 in the lung cancer group and 0.012 in the control group. None of these frequencies in the lung cancer patients were statistically significantly different from the frequencies of the control population. When combining the PCR-typing results (CYP2D6A, CYP2D6B) 20 individuals were found to carry two PM-associated alleles in the lung cancer group (n = 204) compared with only six among the controls (n = 117). This corresponds to a PM frequency of 9.8% in the lung cancer population compared with 5.1% in the control population which is, however, not significantly different from each other. These results are not in concordance with previous results which suggest that the EM-phenotype is a susceptibility marker for lung cancer.

Adult↗
PubMed1994

Analysis of HLA-class-II-encoded antigen-processing genes TAP1 and TAP2 in primary biliary cirrhosis.

The search for genes involved in the aetiology of primary biliary cirrhosis (PBC) has centred on the major histocompatibility complex (MHC) on chromosome 6. Genotyping studies have confirmed an association with HLA class II allele DR8. We investigated polymorphisms in two newly identified genes (TAP1 and TAP2) situated close to the DR locus and thought to encode membrane transporter molecules involved in endogenous antigen processing. Genomic DNA extracted from PBC patients was compared with local healthy controls. TAP1 was analysed by amplification refractory mutation system (ARMS) PCR, and two alleles (A and B) were identified. In 126 PBC patients and 116 controls, allele frequencies were (A:B) 81:19% and 79:21%, respectively (NS). TAP2 analysis was by PCR followed by Bfal restriction digest, and again two alleles (A and B) were identified. Their frequencies in 109 PBC patients and 96 controls were (A:B) 76:24% and 73:27%, respectively (NS). No TAP1-TAP2 haplotype was associated with PBC. TAP allele frequencies were estimated within the DR8 subgroups (22 PBC, 14 controls). B allele frequency for TAP1 was increased in both DR8-positive PBC patients and controls compared with DR8-negative patients and controls (41% vs. 14% in PBC; 43% vs. 18% in controls), but no disease association was found. However, the increased frequency of TAP1B in DR8-positive subjects (42% DR8-positive vs. 16% DR8-negative, p < 0.001) indicates linkage disequilibrium between these two loci.

Base Sequence↗
PubMed1993

Determination of nifedipine in gingival crevicular fluid: a capillary gas chromatographic method for nifedipine in microlitre volumes of biological fluid.

This paper describes a sensitive capillary gas chromatographic (GC) method for the determination of nifedipine in sub-microliter samples of gingival crevicular fluid (GCF) in order to assess if nifedipine is present in the GCF and if so, whether the local tissue concentrations of this drug are an important determinant in the development of gingival overgrowth. Liquid-liquid and solid-phase extraction were combined to give adequate sample clean-up and concentration for measurement by automated capillary GC with electron capture detection. Nifedipine and its principal metabolite, M-I, were analysed in both plasma and GCF in 9 adult male patients who had been taking nifedipine for over six months. M-I could not be measured in GCF. Plasma nifedipine and M-I levels were normal, but the nifedipine levels found in the GCF of 7 patients (including all those with overgrowth) were remarkably elevated, 15 to 316-fold greater. This massive concentration of nifedipine into the GCF is therefore linked with gingival overgrowth. This is the first time that a GC method has been developed which permits determination of GCF pharmacokinetics of a drug which causes gingival overgrowth, and further investigation will lead to a better understanding of the tissue mechanisms involved.

Adult↗
PubMed1993

Pharmacokinetics and metabolism of ifosfamide administered as a continuous infusion in children.

The pharmacokinetics and metabolism of ifosfamide was investigated in a group of 16 pediatric patients (5 girls) aged 1-17 years. Each received a dose of 3 g/m2/day for up to 3 days by continuous infusion. Plasma and urine were collected, and concentrations of ifosfamide and its principal metabolites were determined by a quantitative high-performance thin layer chromatography method. During 3 days of continuous infusion, the plasma concentrations of parent drug decreased. This was accompanied by a continuous increase in dechloroethylated products in plasma but not in urine. Estimated pharmacokinetic parameters (clearance, volume of distribution, and half-life) were dependent on body size and age but not any other patient variable. Renal clearance was a relatively minor route of elimination for parent drug and corresponded to < 25% of glomerular filtration rate. Metabolite data from plasma and urine indicated a high degree of interindividual variation in metabolism. Comparison of metabolite recoveries in urine indicated a positive correlation between activation and inactivation routes of metabolism. Prior exposure to ifosfamide was associated with a higher recovery in urine of dechloroethylated metabolites. The severity of hematological toxicity was inversely correlated with glomerular filtration rate but not to parameters of ifosfamide metabolism. There was marked variation in levels of the carboxy metabolite, which could not be detected in the plasma of 5 subjects. However, evidence for a polymorphism in metabolism to this metabolite was weaker than that seen with the isomeric oxazaphosphorine cyclophosphamide. There appeared to be a higher clearance of ifosfamide in pediatric patients compared to adults. The significance of this, and of the variation in metabolism of ifosfamide, for clinical outcome remains to be established, but the increase in the dechloroethylation route of metabolism may be associated with an increased risk of toxicity.

Adolescent↗
PubMed1993

Induction of drug-metabolizing enzymes in human pancreatic cancer and chronic pancreatitis.

Chronic pancreatitis and pancreatic cancer have both been linked with occupational exposure to organic chemicals. These chemicals are known to be metabolized within the liver by the cytochrome P-450 family of enzymes, and indeed are able to induce levels of these enzymes as evidence of their interaction. The purpose of this study was therefore to see if these enzyme systems were altered in chronic pancreatitis and pancreatic cancer. Immunocytochemistry of four phase I drug-metabolizing enzymes (cytochromes P-450 IIIA1, P-450 IIE, P-450 IA2, and NADPH cytochrome P-450 oxido-reductase) and one phase II enzyme [glutathione S-transferase (GST) 5-5] was therefore performed on pancreas and/or liver biopsy samples from organ donors and compared with patients with chronic pancreatitis or pancreatic cancer. In samples from donor subjects, the types and levels of drug-metabolizing enzymes in hepatocytes were similar to those seen in pancreatic acinar cells. In material from patients with chronic pancreatitis or pancreatic cancer, cytochrome P-450 enzyme levels were greater in both the liver and the pancreas than those seen in the donor group, while GST levels were unchanged. Islets of Langerhans showed high levels of P-450 IA2 in the donor group, with clear induction of P-450 IIIA1 and NADPH cytochrome P-450 oxidoreductase in patients with chronic pancreatitis but not in the pancreatic cancer group. Levels of GST 5-5 were also induced in the islets. The present findings raise the possibility of an aetiological relationship between elevated levels of drug-metabolizing enzymes and the subsequent development of disease.

Aryl Hydrocarbon Hydroxylases↗