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Biomedical subjects

J R Idle

Publications and source records attributed to J R Idle.

At least 19 recordsLinked to original sources
PubMed1998

Variability of coumarin 7- and 3-hydroxylation in a Jordanian population is suggestive of a functional polymorphism in cytochrome P450 CYP2A6.

OBJECTIVE: To determine the variability of coumarin 7- and 3-hydroxylation in a human population and to evaluate the evidence for the existence of genetic polymorphism in these pathways. 7-Hydroxylation of coumarin is considered to be a detoxication pathway, whilst 3-hydroxylation, which predominates in rats, leads to hepatotoxicity in the rat. Coumarin metabolic phenotypes could aid in refining the risk evaluation for humans of dietary and environmental exposure to coumarin and for the chronic use of coumarin in high doses as a drug to treat lymphoedema and certain cancers. METHODS: Healthy male and female Jordanian volunteers (n = 103) were administered 2 mg coumarin by mouth and collected their 0-8-h urines. These, together with pre-dose blank urines, were analysed by selected-ion monitoring gas chromatography mass spectrometry for their content of the coumarin metabolites 7-hydroxycoumarin (70HC) and 2-hydroxyphenylacetic acid (2OHPAA), the latter arising from the 3-hydroxylation pathway. RESULTS: After coumarin administration, excretion of both 70HC and 2OHPAA was highly variable. A coumarin metabolic ratio (2OHPAA/7OHC) was suggestive of polymorphism. At least one subject had a metabolic response similar to an individual known to be both phenotypically and genotypically (CYP2A6 gene) 7-hydroxylation-deficient. CONCLUSION: In the light of the finding of high variability and possible polymorphism in both the 7- and 3-hydroxylation of coumarin in a human population. we recommend a reappraisal of the risk evaluation of human exposure to coumarin, particularly in pharmaceutical doses.

Adult↗
PubMed1998

CYP2D6 phenotype-genotype relationships in African-Americans and Caucasians in Los Angeles.

CYP2D6 genotyping (CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*13, CYP2D6*16 alleles and gene duplications) was previously performed on 1053 Caucasian and African-American lung cancer cases and control individuals and no significant difference in allele frequencies between cases and control individuals detected. We have carried out additional genotyping (CYP2D6*6, CYP2D6*7, CYP2D6*8, CYP2D6*9, CYP2D6*10, CYP2D6*17 alleles) and debrisoquine phenotyping on subgroups from this study to assess phenotype-genotype relationships. African-Americans showed significant differences from Caucasians with respect to frequency of defective CYP2D6 alleles, particularly CYP2D6*4 and CYP2D6*5. The CYP2D6*17 allele occurred at a frequency of 0.26 among 87 African-Americans and appeared to explain higher average metabolic ratios among African-Americans compared with Caucasians. CYP2D6*6, CYP2D6*8, CYP2D6*9 and CYP2D6*10 were rare in both ethnic groups but explained approximately 40% of higher than expected metabolic ratios among extensive metabolizers. Among individuals phenotyped with debrisoquine, 32 out of 359 were in the poor metabolizer range with 24 of these (75%) also showing two defective CYP2D6 alleles. Additional single strand conformational polymorphism analysis screening of samples showing large phenotype-genotype discrepancies resulted in the detection of three novel polymorphisms. If subjects taking potentially interfering drugs were excluded, this additional screening enabled the positive identification of 88% of phenotypic poor metabolizers by genotyping. This sensitivity was comparable with that of phenotyping, which identified 90% of those with two defective alleles as poor metabolizers.

Base Sequence↗
PubMed1997

CYP2E1 genetic polymorphisms and risk of nasopharyngeal carcinoma in Taiwan.

BACKGROUND: Nasopharyngeal carcinoma occurs disproportionately among individuals of Chinese descent. The cytochrome P450 2E1 enzyme (CYP2E1) is known to activate nitrosamines and other carcinogens that are possibly involved in the development of this disease. Certain alleles of the CYP2E1 gene are thought to be more highly expressed than others, and their distribution varies between Asian and Caucasian populations. We conducted a case-control study to investigate whether such variations affect the risk of developing nasopharyngeal cancer. METHODS: Three hundred sixty-four patients with nasopharyngeal carcinoma (96% of 378 eligible patients) and 320 control subjects (86% of 374 eligible subjects) were studied. A risk factor questionnaire was administered to participants to assess factors postulated to be linked to nasopharyngeal carcinoma. Peripheral blood was obtained from all subjects and DNA was purified from nucleated cells. A polymerase chain reaction-based restriction fragment length polymorphism assay that used the restriction enzymes Rsa I and Dra I was used to detect wild-type and variant forms of the CYP2E1 gene. RESULTS: Individuals homozygous for an allele of the CYP2E1 gene that is detected by Rsa I digestion (c2 allele) were found to have an increased risk of nasopharyngeal carcinoma (relative risk [RR] = 2.6; 95% confidence interval [CI] = 1.2-5.7); this effect was limited to nonsmokers (RR = 9.3; 95% CI = 2.7-32) and was not affected by alcohol consumption. CONCLUSIONS: Our findings suggest that the CYP2E1 genotype is a determinant of nasopharyngeal carcinoma risk.

Adult↗
PubMed1997

A single amino acid substitution (Leu160His) in cytochrome P450 CYP2A6 causes switching from 7-hydroxylation to 3-hydroxylation of coumarin.

Human populations are thought to metabolize coumarin almost exclusively by 7-hydroxylation. We have identified an individual who is homozygous for a single amino acid substitution (Leu160His) in the cytochrome P450 CYP2A6 arising from the variant CYP2A6*2 allele. On administration of coumarin (2 mg orally) no detectable 7-hydroxycoumarin was excreted in the 0-8-hr urine, rather, approximately 50% of the dose was eliminated as 2-hydroxyphenylacetic acid, the end-product of coumarin 3-hydroxylation. His immediate family members, who were heterozygous for the CYP2A6*2 allele, excreted little 2-hydroxyphenylacetic acid and mainly 7-hydroxycoumarin, when similarly tested. These findings raise a question regarding human risk evaluations for environmental coumarin exposures, since 7-hydroxylation is regarded as a detoxication pathway, but 3-hydroxylation as the process required to lead to macromolecular covalent binding of coumarin. Persons homozygous for the CYP2A6*2 allele may constitute 1-25% of various populations.

Adolescent↗
PubMed1997

Genetic polymorphism of CYP2D6 and lung cancer risk in African-Americans and Caucasians in Los Angeles County.

The well described genetic polymorphism of the CYP2D6 gene influences response to a wide variety of therapeutic agents metabolized by the CYP2D6 enzyme product. CYP2D6 also appears to play a role, along with other cytochrome P450 enzymes, in the metabolic activation of the tobacco specific nitrosamine, NNK, as well as metabolism of nicotine to cotinine. While impaired activity of CYP2D6 was strongly protective against lung cancer in some studies, primarily based on phenotyping, the literature is conflicting. The molecular basis of CYP2D6 deficiency is now well understood, enabling the use of genotyping to classify individuals. We therefore examined whether lung cancer risk is reduced by the presence of four CYP2D6 alleles associated with impaired activity due to an inactivating mutation--CYP2D6*4, CYP2D6*3, CYP2D6*5 and CYP2D6*16--among 341 incident cases of lung cancer and 710 population controls of Caucasian or African-American ethnicity in Los Angeles County, California. We did not confirm a strong association between the presence of these inactivating alleles and lung cancer risk [odds ratio (OR) = 0.90, 95% confidence interval (CI) 0.60-1.35 for Caucasians], although there was a small decreased risk among the African-Americans (OR = 0.66, 95% CI 0.38-1.14). Among smokers, when the data are stratified according to lifetime smoking history, there is a suggestion of an association limited to Caucasian smokers of <35 pack-years, the median for all smokers in these data (OR = 0.49, 95% CI 0.23-1.04). However, among African-American smokers, who smoke less than Caucasians, the association did not differ between smoking categories. We also examined the possible role of additional copies of the CYP2D6 gene, which lead to enhanced CYP2D6 activity, in increasing lung cancer risk. Among controls the prevalence of having more than two copies of the CYP2D6 gene and no inactivating alleles was 4.3% for Caucasians and 4.9% for African-Americans. Relative to subjects with an inactivating allele, those with an additional copy of the CYP2D6 gene and no inactivating alleles may be at increased risk of lung cancer, particularly for adenocarcinoma (OR = 3.61, 95% CI 1.08-11.7 for African-Americans and OR = 2.20, 95% CI 0.69-6.0 for Caucasians). Our data suggest that the CYP2D6 genetic polymorphism is not the strong risk factor for lung cancer suggested by some studies of phenotype, but may play a minor role.

Adult↗
PubMed1997

Lack of correlation between phenotype and genotype for the polymorphically expressed dihydropyrimidine dehydrogenase in a family of Pakistani origin.

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in pyrimidine catabolism. DPD deficiency is associated with an increased risk of toxicity in cancer patients receiving 5-fluorouracil (5-PU) treatment. DPD deficiency causes an inborn error of metabolism called thymine-uraciluria that is in some instances associated with convulsive disorders and developmental delay in children. We have studied the molecular mechanism accounting for DPD deficiency in a Pakistani pedigree having 2-year-old child with thymine-uraciluria and exhibiting some degree of motor impairment and developmental delay. A common splice mutation was found in the patient's dihydropyrimidine dehydrogenase (DPYD) gene that produces a mutant mRNA resulting in the complete lack of DPD protein and activity in lymphocytes and primary fibroblast. This trait segregated in the family following a typical Mendelian distribution. Surprisingly, the patient's brother also had thymine-uraciluria and was homozygous for the splicing mutation but was clinically asymptomatic. Sequence tagged sites (STS) linkage analyses within 5 megabases of telomeric and centromeric DNA surrounding the DPYD gene revealed no allelic polymorphism between the two brothers. These results suggest that DPD deficiency might not be the only cause of the more severe clinical phenotypes observed in certain thymine-uraciluria patients and that an incomplete correlation between phenotype and genotype is present in the population.

Child, Preschool↗
PubMed1997

Antipsychotic drug-induced movement disorders in schizophrenics in relation to CYP2D6 genotype.

BACKGROUND: Approximately 5-10% of Caucasians (poor metabolisers) show impaired metabolism of at least 20 therapeutically important drugs, including a number of commonly used antipsychotic agents, because they lack the cytochrome p450 enzyme CYP2D6. The molecular basis of this defect is now well understood and simple genotyping tests using the polymerase chain reaction (PCR) have been developed. METHOD: To determine whether poor metabolisers are more susceptible to acute dystonic reactions and chronic movement disorders associated with the administration of antipsychotic drugs, we determined CYP2D6 genotypes in a group of 76 schizophrenics using previously described methods involving PCR and restriction fragment length polymorphism analysis. RESULTS: There was no difference in genotype frequencies between the schizophrenics and a normal control population, suggesting that CYP2D6 genotype was not a factor in determining susceptibility to the disease. However, four of the five poor metabolisers compared with 44% of the remaining subjects were suffering from a movement disorder at the time of the study, although because of the small number of poor metabolisers in the group the difference was not statistically significant. Poor metabolisers were not more likely to suffer an acute dystonic reaction. CONCLUSIONS: CYP2D6 genotype is not a determinant of susceptibility to acute dystonic reactions but may be a contributory factor in antipsychotic drug-induced movement disorders including tardive dyskinesia.

Antipsychotic Agents↗
PubMed1996

Ultrarapid metabolizers of debrisoquine: characterization and PCR-based detection of alleles with duplication of the CYP2D6 gene.

Up to 7% of Caucasians may demonstrate ultrarapid metabolism of debrisoquine due to inheritance of alleles with duplicated functional CYP2D6 genes. Here we describe the genomic organization of the duplicated CYP2D6 genes in the 42 kb XbaI allele. We postulate that this duplication originates from a homologous, unequal cross-over event which involved two 29 kb XbaI wild-type alleles, and had break points within a 2.8 kb direct repeat (CYP-REP) flanking the CYP2D6 gene. Moreover, we have designed two different PCR assays for detection of alleles with duplicated CYP2D6 genes. Both assays correctly identified 29 out of 29 subjects positive for the 42 kb XbaI allele. No false negative or false positive reactions were observed.

Alleles↗
PubMed1996

Automated gas chromatographic assay for amlodipine in plasma and gingival crevicular fluid.

This paper describes an automated capillary gas chromatographic method for the determination of amlodipine in plasma, and in sub-microlitre volumes of gingival crevicular fluid (GCF), in order to assess if amlodipine is present in GCF under conditions of gingival overgrowth, as has been shown for nifedipine, another dihydropyridine drug. Liquid-liquid extraction followed by derivatisation was employed to isolate amlodipine and render it suitable for gas chromatography. Amlodipine was analysed in plasma and GCF of four patients undergoing amlodipine therapy for cardiovascular disorders, three of whom had significant gingival overgrowth. Amlodipine was detected in the plasma of all patients and in massive concentrations in the GCF of those patients with overgrowth, 23- to 290-fold greater than in their plasma. Like nifedipine, amlodipine sequestration into GCF appears to be linked with gingival overgrowth.

Amlodipine↗
PubMed1996

Intrasubject variation in children of ifosfamide pharmacokinetics and metabolism during repeated administration.

The aim of this study was to investigate intrasubject variability in ifosfamide (IFO) pharmacokinetics and metabolism which may influence clinical effect, since the pharmacology of this drug is dependent on metabolism. A group of 11 patients (ages 1-16 years) were studied on at least two occasions. IFO, 9 gm-2 was administered as a continuous infusion over 72 h. Plasma and urine samples were collected and concentrations of IFO and its metabolites were determined. Comparisons were made between courses in the same subject, allowing for differences in age and prior IFO treatment. There was a wide variation in drug (twofold) and metabolite (up to tenfold) AUCs between courses in the same patient. Although some patients did show an increase in clearance between courses (up to threefold), there was no significant consistent change in overall pharmacokinetics among the different courses studied in the same patient. There was a significant decrease (up to 63%) in the AUC of the inactive metabolite 3-dechloroethylifosfamide (3-DCI) in later courses compared with the first course studied (P = 0.032, paired t-test). This was matched by an increase in the AUC of the total dechloroethylated metabolites with course (P = 0.015, paired t-test). None of the other metabolites measured showed any consistent change in plasma or urine levels between courses. Overall, the AUC of parent drug correlated with age (r2 = 0.86, P = 0.011), and postinfusion half-life correlated with plasma bilirubin (r2 = 0.89, P = 0.007). This study demonstrated large and seemingly unpredictable intrasubject variability in IFO pharmacokinetics and metabolism during repeated administrations. Investigations relating the clinical effects of IFO to pharmacokinetics and metabolism must take this variation into account.

Adolescent↗
PubMed1996

Ifosfamide nephrotoxicity: limited influence of metabolism and mode of administration during repeated therapy in paediatrics.

This study investigated the relationship between both acute and chronic nephrotoxic effects of ifosfamide (IFO) and its metabolism. 15 paediatric patients (4 girls) were investigated. Each received 6-9 g/m2 IFO over 15 days, repeated every 3 weeks for up to 16 courses. The pharmacokinetics and metabolism of IFO were measured during its administration, either as a continuous 72 h infusion or as three bolus doses of 3 g/m2 on consecutive days. In 8 patients, the metabolism of IFO was investigated during one early course and one late course to determine the magnitude of any changes following repeated administration. Acute measures of renal toxicity were not correlated with any of the IFO pharmacokinetic or metabolic parameters in the same course, whether the drug was administered as a bolus or by continuous infusion. Chronic renal toxicity, determined 1 month (n = 13) or 6 months (n = 8) after treatment, did not correlate with any of the IFO pharmacokinetic or metabolic parameters in any individual course of treatment. The overall degree of nephrotoxicity, however, was correlated with the changes in metabolism between late and early courses (n = 8). There was a negative correlation between the change in area under the curve of the dechloroethylated metabolites of IFO and the overall nephrotoxicity at 1 month or 6 months after treatment (both r2 = 0.66, P = 0.014). The results imply that patients in whom metabolism via dechloroethylation decreases are at a greater risk of chronic nephrotoxicity. This is contrary to the hypothesis that the systemic production of chloroacetaldehyde is the mechanism by which IFO causes nephrotoxicity. The importance of acute and chronic changes in renal function for long-term outcome remains to be determined.

Acute Disease↗
PubMed1996

Lung cancer risk in relation to the CYP2E1 Rsa I genetic polymorphism among African-Americans and Caucasians in Los Angeles County.

Genetic polymorphisms in the activation or detoxication of carcinogens, such as those in tobacco smoke, may produce differences in individual susceptibility to lung cancer. The cytochrome P450 CYP2E1 is an enzyme involved in the metabolism of nitrosamines in tobacco smoke. A polymorphism of CYP2E1 detectable by the restriction enzyme Rsa I may be functionally important because it is located in a putative binding site for the transcription factor HNF-1 and has been associated with higher levels of CYP2E1 transcription. It is conceivable that this CYP2E1 Rsa I polymorphism might contribute to differences in susceptibility to lung cancer. We conducted a case-control study of patients with incident lung cancer and population controls in Los Angeles County to examine the association between the CYP2E1 Rsa I polymorphism and lung cancer risk among African-Americans and Caucasians. Samples of white blood cell DNA sufficient for determination of the CYP2E1 Rsa I genotype by a polymerase chain reaction-based assay were obtained from 341 cases and 706 controls with data on lifetime smoking history. No subjects were homozygous for the CYP2E1 Rsa I rare c2 allele. The rare c2 allele was not associated with an increased risk of lung cancer (adjusted odds ratio, OR 0.72; 95% confidence interval, CI = 0.35-1.46). Among the population controls the percentage of subjects carrying the rare c2 allele was lower (p = 0.002) among African-Americans (2%) compared with Caucasians (8%). However, the association between the CYP2E1 Rsa I genotype and lung cancer risk did not differ between ethnic groups. There was no important association between the CYP2E1 Rsa I genotype and lung cancer risk in analyses stratified by cell-type, smoking history, gender, occupational asbestos exposure, and dietary intake of antioxidants vitamin C, vitamin E or beta carotene. Due to the low frequency of the c2 allele in these populations, larger studies would be necessary to rule out a modest association between the CYP2E1 Rsa I polymorphism and lung cancer risk.

Adult↗