Characterization of the 16+9 kb and 30+9 kb CYP2D6 XbaI haplotypes.
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Africa, Northern↗
Biomedical subjects
J R Idle
Publications and source records attributed to J R Idle.
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↗
Lung cancer risk in relation to the CYP2C9 genetic polymorphism among Caucasians in Los Angeles County.
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Aryl Hydrocarbon Hydroxylases↗
CYP2D6 genotype and smoking behaviour in cigarette smokers.
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Cytochrome P-450 CYP2D6↗
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↗
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↗
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↗
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↗
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↗
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↗
Nomenclature for human CYP2D6 alleles.
To standardize CYP2D6 allele nomenclature, and to conform with international human gene nomenclature guidelines, an alternative to the current arbitrary system is described. Based on recommendations for human genome nomenclature, we propose that alleles be designated by CYP2D6 followed by an asterisk and a combination of roman letters and arabic numerals distinct for each allele with the number specifying the key mutation and, where appropriate, a letter specifying additional mutations. Criteria for classification as a separate allele and protein nomenclature are also presented.
Alleles↗
CYP2D6 genotypes in cigarette smokers and non-tobacco users.
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Adult↗
Characterization and PCR-based detection of two different hybrid CYP2D7P/CYP2D6 alleles associated with the poor metabolizer phenotype.
The majority of humans deficient in the cytochrome P450 CYP2D6 enzyme, so-called poor metabolizers (PMs), can now be identified by genotyping for several different PM-associated mutations. However, additional null alleles remain to be identified as demonstrated by subjects with the PM phenotype in the absence of a corresponding genotype. The rare 11 kb band on Xba I RFLP analysis, which is distinct from the 13 kb CYP2D6D (CYP2D6*5) allele, has been proposed to constitute such a unique non-functional allele. Here we demonstrate that the 11 kb band represents at least two different nine exon CYP2D7P/CYP2D6 hybrids generated by large deletions in the CYP2D gene cluster due to unequal cross-over or looping-out mechanisms. The total allele frequency was approximately 0.001-0.01 in European and North American Caucasians. The most common variant (CYP2D6*16) had breakpoints lying between the end of exon 7 and the start of exon 9 of the respective genes. The "CYP2D7-like' part of the gene was most homologous to the previously described CYP2D7AP and CYP2D7 (44/11.5) sequences. The other chimeric allele consisted of exon 1 of CYP2D7 and exons 2-9 from CYP2D6, and may be similar to a hybrid gene termed CYP2D6*13 recently described in a French individual. Two different routine PCR assays were developed for rapid and sensitive detection of these alleles, namely amplification of a 8 kb fragment from both CYP2D6*13 and CYP2D6*16, together with a CYP2D6*16-specific method which gave a 1.4 kb PCR product. The 8 kb assay for the CYP2D6*13 and CYP2D6*16 alleles also produced a 9.5 kb fragment in samples positive for the 13 kb CYP2D6*5 allele. Therefore, it is now possible to screen for the large CYP2D gene deletions by a single long PCR method.
Alleles↗
Lung cancer risk in relation to the CYP2C9*1/CYP2C9*2 genetic polymorphism among African-Americans and Caucasians in Los Angeles County, California.
CYP2C9 is involved in the metabolism of warfarin and a wide array of other therapeutic agents. It also appears to play a role, along with other cytochrome P450 enzymes, in the metabolism of benzo[a]pyrene, a carcinogen in tobacco smoke. A relatively common allelic variant (termed R144C, Cys144 or more recently CYP2C9*2) has been described that results in the substitution of cysteine for arginine at residue 144 and appears to reduce enzyme activity. We therefore examined the possible association between the presence of the CYP2C9*2 variant allele and risk of lung cancer using peripheral blood DNA from 329 incident cases of lung cancer (152 African-American and 177 Caucasian) and 700 (239 African-American and 461 Caucasian) population controls in Los Angeles County, California. Among the population controls the frequency of the CYP2C9*2 variant allele was lower (p = 0.00002) among African-Americans (0.036) than among Caucasians (0.100). The presence of the CYP2C9*2 variant allele was not associated with a decreased risk of lung cancer; slight but nonstatistically significant elevations in risk were observed for both African-Americans [odds ratio (OR) 1.22, 95% confidence interval (CI) 0.48-3.11] and Caucasians (OR = 1.55, 95% CI 0.96-2.48). The ORs were slightly and nonsignificantly elevated for all histologic types without substantive variation. The association also did not vary materially according to smoking history or whether subjects had the homozygous deletion of the GSTM1 gene. We found no support for the hypothesis that the CYP2C9*2 variant allele decreases the risk of lung cancer. The role of P450s, including CYP2C9, in benzo[a]pyrene metabolism is not fully defined, and CYP2C9 catalyses detoxication as well as activation steps. Thus it is not inconceivable that diminished CYP2C9 activity could increase metabolic activation of benzo[a]pyrene to carcinogenic intermediates. Nonetheless, the small increased risk associated the CYP2C9*2 variant allele in our data is consistent with chance and should not be overinterpreted.
Adenocarcinoma↗
Cyclophosphamide pharmacokinetics in children.
1. Cyclophosphamide pharmacokinetics were measured in 38 children with cancer. 2. A high degree of inter-patient variation was seen in all pharmacokinetic parameters. Cyclophosphamide half-life varied between 1.1 and 16.8 h, clearance varied between 1.2 and 10.61 h-1 m-2 and volume of distribution varied between 0.26 and 1.48 1 kg-1. 3. The half-life of cyclophosphamide was prolonged at high dose levels (P = 0.008). 4. Children who had received prior treatment with dexamethasone showed a mean increase in clearance of 2.51 h-1 m-2 (P = 0.001) presumably as a result of CYP450 enzyme induction. 5. Treatment with allopurinol or chlorpromazine was associated with a significant increase in cyclophosphamide half-life (P < 0.001 in both cases). 6. Dose and concurrent treatment may influence cyclophosphamide metabolism in vivo and thus potentially alter the drugs therapeutic effect.
Adolescent↗
Relationship between genotype for the cytochrome P450 CYP2D6 and susceptibility to ankylosing spondylitis and rheumatoid arthritis.
OBJECTIVES: To determine whether particular genotypes for the cytochrome P450 enzyme CYP2D6, a polymorphic enzyme, are associated with susceptibility to ankylosing spondylitis (AS) and rheumatoid arthritis (RA), or linked with any specific clinical or familial features of the two conditions. METHODS: CYP2D6 genotypes were determined in 54 patients with AS, 53 patients with RA, and 662 healthy controls. Leucocyte DNA was analysed for the presence of mutations by restriction fragment length polymorphism analysis with the restriction enzyme Xbal and by two separate polymerase chain reaction assays. RESULTS: On the basis of odds ratio (OR), individuals with two inactive CYP2D6 alleles were more susceptible to AS than controls (OR 2.71, 95% confidence interval (CI) 1.04 to 7.08), with a stronger effect for the CYP2D6B allele (OR 4.11, 95% CI 1.54 to 11.0). No significant differences in the distribution of overall genotypes and allele frequencies were observed between RA and controls. No significant relationships were found between the skeletal, extraskeletal or familial features of AS or RA (iritis, psoriasis, inflammatory enteropathy and rheumatoid nodules, kerato-conjunctivitis sicca, pleuritis, rheumatoid and antinuclear factors) and the overall genotype. CONCLUSIONS: Our findings suggest a modest association between homozygosity for inactive CYP2D6 alleles, particularly CYP2D6B alleles, and susceptibility to AS. However, our results fail to demonstrate a genetic link between CYP2D6 genotype and RA.
Aged↗
CYP2D6 allelic frequencies in young-onset Parkinson's disease.
Parkinson's disease (PD) is thought to develop as a result of interactions between genetic susceptibility factors and environmental exposures. One candidate gene is CYP2D6, which codes for the debrisoquine 4-hydroxylase cytochrome P450. Impairment of debrisoquine 4-hydroxylase activity has been associated with an increased risk of PD in patients with younger age at disease onset. Genotyping studies in patients with an older age at onset have reported modest increases in risk associated with the CYP2D6 B and A alleles; however, the risk for young-onset PD has not been adequately evaluated. We designed a case-control study to investigate the role of nonfunctional CYP2D6 allelic risk factors for young-onset PD in a sizable patient population and compared the distributions of CYP2D6 genotypes between young-onset ( < or = 51 years) PD patients (n = 108) and controls (n = 236). In contrast with the results from genotyping studies conducted among patients with an older age at onset, there were no significant differences in CYP2D6 allelic frequencies between young-onset PD cases and controls. The frequency of the B allele was slightly lower in the young-onset PD cases than in the controls (0.14 versus 0.20) (X2 = 2.66, p = 0.10). The presence of one or more B alleles was not associated with an increased risk of young-onset PD (odds ratio 0.58; 95% CI 0.33 to 1.00), nor was the presence of one or more nonfunctional alleles (i.e., A, B, D, and D2) (odds ratio 0.68; 95% CI 0.41 to 1.13). This study suggests that the young-onset PD population may differ from the older-onset population with respect to risk factors.
Age of Onset↗