Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.30.2 (endonuclease)
 18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The debrisoquine/sparteine polymorphism is associated with a clinically important genetic deficiency of oxidative drug metabolism. From 5% to 10% of Caucasians designated as poor metabolizers (PMs) of the debrisoquine/sparteine polymorphism have a severely impaired capacity to metabolize more than 25 therapeutically used drugs. The impaired drug metabolism in PMs is due to the absence of cytochrome P450IID6 protein. The gene controlling the P450IID6 protein, CYP2D6, is located on the long arm of chromosome 22. A pseudogene CYP2D8P and a related gene CYP2D7 are located upstream from CYP2D6. This gene locus is highly polymorphic. After digestion of genomic DNA with XbaI endonuclease, restriction fragments of 11.5 kb and 44 kb represent mutant alleles of the cytochrome CYP2D6 gene locus associated with the PM phenotype. In order to elucidate the molecular mechanism of the mutant allele reflected by the XbaI 11.5-kb fragment, a genomic library was constructed from leukocyte DNA of one individual homozygous for this fragment and screened with the human IID6 cDNA. The CYP2D genes were isolated and characterized by restriction mapping and partial sequencing. We demonstrate that the mutant 11.5-kb allele results from a deletion involving the entire functional CYP2D6 gene. This result provides an explanation for the total absence of P450IID6 protein in the liver of these PMs.
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PMID:Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. 167 90

Gene cluster CYP2D controls the biosynthesis of enzyme CYP2D6, which is responsible for the polymorphic oxidation of sparteine, debrisoquine and related drugs. This cluster consists of the functional gene D6 and of two pseudogenes, D7 and D8. RFLP Bam HI analysis of CYP2D in 37 unrelated and eight related Ngawbe Guaymi Amerindians of Panama showed a polymorphism characterized by the presence of two alleles: 4.7 + 7.9 and 2.3 + 6.0 (frequencies: 0.63 and 0.37, respectively, n = 35 unrelated subjects). The possible genotypes for these alleles follow the Hardy-Weinberg distribution (chi 2 = 1.76; 0.10 < p < 0.25). All PMs of sparteine or debrisoquine (n = 7) were homozygotes for the second allele, but not all homozygotes (n = 10) were PMs, so there was not an exclusive association between the Bam HI genotype and the observed phenotype. A similar analysis with the endonuclease Xba I proved to be non-informative in relation to phenotype, since all subjects (n = 40) showed only the 29 kb allele. Allele-specific PCR studies of selected subjects indicated the existence of the CYP2D6B allele (freq = 0.17; C.I.95% = 0.085, 0.29; n = 30 unrelated subjects), in addition to the wild-type. The mutant CYP2D6B allele was responsible for the enzyme deficiency present in PMs. Its presence in Amerindians suggests that this allele has a far more ancient evolutionary history than previously thought. The over-all RFLP and PCR analyses point to a diminished genetic diversity for the Ngawbe subjects, consistent with their demographic history and population genetics.
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PMID:Evolutionary pharmacogenetics of CYP2D6 in Ngawbe Guaymi of Panama: allele-specific PCR detection of the CYP2D6B allele and RFLP analysis. 790 9

Previous studies have shown that many neuroleptics are metabolized by debrisoquine 4-hydrolase (CYP2D6), which exhibits genetic polymorphisms. In Oriental populations, poor metabolizers (PMs) with a lack of CYP2D6 activity are rare, although the CYP2D6*10 allele, which is associated with decreased CYP2D6 activity, is commonly found. The authors examined the relationship between tardive dyskinesia (TD) and CYP2D6 polymorphisms, including the CYP2D6*10 allele. Subjects consisted of 100 Japanese schizophrenics. TD was evaluated using the Abnormal Involuntary Movement Scale (AIMS). Genotyping for the presence of the CYP2D6*3, CYP2D6*4 and CYP2D6*10 alleles was performed using allele-specific PCR amplification and endonuclease digestions. The frequency of the CYP2D6*10 allele was 0.52, and only one allele showed the PM genotype. There was a significant difference in the allelic distribution of CYP2D6*10 between subjects with and without TD. We also found significant genotypic and allelic associations with dichotomized total AIMS scores of 6 or more (moderate or severe abnormal movements) and with scores of less than 6 (mild or no movements). After these associations were adjusted for confounding variables (gender, age, duration of illness and neuroleptic dose) by regression analysis, the CYP2D6*10 genotype showed significant association with the total AIMS score, and a modest association with TD occurrence. These results indicate that the CYP2D6*10 genotype may play a role in the development of moderate or severe abnormal movements.
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PMID:Tardive dyskinesia and debrisoquine 4-hydroxylase (CYP2D6) genotype in Japanese schizophrenics. 971 6

The molecular basis of the reduced ability of a Chinese to metabolize debrisoquine was explored by sequencing all of the nine exons of the CYP2D6 gene. The subject has T188, A1846, T2938, and C4268 (CYP2D6*14) instead of C188, G1846, C2938, and G4268 as in wild-type subjects. XbaI restriction fragment length polymorphism indicated that the subject has a 29-kb allele and a gene deletion (11.5 kb) in another allele (CYP2D6*5). A CYP2D6*14 allele together with a CYP2D6*5 allele may cause the poor metabolism of the subject. T188, T2938, and C4268 are common haplotypes in Chinese-extensive metabolizers. The effect of G1846 to A mutation in CYP2D6 metabolism has not been reported. A polymerase chain reaction-based endonuclease digestion test was designed for the G/N1846 polymorphism and 124 Chinese subjects were screened. With DNA sequencing, two other subjects showed the heterozygous G/A1846 and have a relatively high metabolic ratio of debrisoquine hydroxylation. The site-directed mutagenesis was used to create recombinant CYP2D6 cDNA with T188, A1846, or C4268. The cDNA was then transfected into Rat-1 cells. The transfection was confirmed by Southern, Northern, and Western blots. Based on the same microsomal protein level, the bufuralol 1'-hydroxylation activity of CYP2D6(T188) or CYP2D6(A1846) was significantly lower than that of the wild-type CYP2D6. P34S mutation (C188 to T) significantly decreased CYP2D6 activity. G169R mutation (G1846 to A) also decreased CYP2D6 activity and may further reduce the metabolic activity of CYP2D6 protein with P34S, R296C, and S486T mutations.
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PMID:G169R mutation diminishes the metabolic activity of CYP2D6 in Chinese. 1006 70

The purpose of this study was to establish the frequencies of CYP1A1 and CYP2D6 polymorphic genotypes in the Tundra Nentsi population, which is a small indigenous northern people living in Siberia and belonging to the Northern Mongoloid race. The frequencies of Ile/Ile, Ile/Val, and Val/Val genotypes in the Tundra Nentsi population, as determined by means of the allele-specific PCR, were 50.8%, 39.2%, and 10%, respectively. Thus, the Val allele frequency in Tundra Nentsi appeared to be as high (29.5%) as in the Japanese population (25%) reported elsewhere. Those frequencies in the reference group of Siberian Caucasians were in good agreement with the data reported elsewhere for other Caucasians, although the Val allele frequency observed in Siberia inhabitants (5.7%) was somewhat higher than those frequencies obtained for other Caucasian populations. By means of PCR followed by specific-site digestion with MvaI endonuclease, we analysed the frequencies of CYP2D6B allele in the Tundra Nentsi population. The frequencies of 2D6wt/2D6wt and 2D6wt/B in the group of 120 Nentsi were 84.2% and 15.8%, respectively, with no subject possessing the 2D6B/2D6B genotype. The group of Siberian Caucasians represented those frequencies as 67.7%, 27.1%, and 5.2%, respectively. In total, the frequency of CYP2D6B allele in the Tundra Nentsi population was half that in Caucasians (8.3% vs. 19%). Taken together, our data indicate that the frequencies of CYP2D6B and Val allele of CYP1A1 in Tundra Nentsi population are different from those obtained for Caucasians. We also found similarities in the CYP1A1 mutation frequencies in the Tundra Nentsi and Japanese populations.
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PMID:Genetic polymorphism of CYP1A1 and CYP2D6 in the Tundra Nentsi population of Siberia. 1009 78

To establish adapter-ligation mediated allele-specific amplification ("ALM-ASA" for short) for multiplex SNP genotyping, five SNPs, 100C>T, 1661G>C, 1758G>T, 2470T>C and 2850C>T in CYP2D6 gene were used as an example for evaluating the method. Firstly, a preamplification was carried out for producing a long target containing all SNPs of interest. Secondly, the preamplified DNA fragments were digested with a restriction endonuclease to form sticky ends. Thirdly, an adapter was ligated to either end of the digested fragment. One end of the adapter was designed as a sequence sticky to the ends of the enzymatically digested fragments, and the other end had a common sequence. Fourthly, an allele-specific amplification was performed by allele-specific primers and a universal primer in one tube by using the adapter-ligated fragments as templates. Finally, the allele-specific amplification products were separated by agarose gel electrophoresis. Because each tube corresponds to one kind of allele-specific primers, the genotype of an SNP can be easily discriminated by the length of the amplified products in each tube. The products of 5-plex allele-specific amplification can be separated by agarose gel electrophoresis. Five SNPs in the CYP2D6 gene were successfully typed for 20 healthy Mainland Chinese and the results were in agreement with those by RFLP. By ALM-ASA, n+1 primers (n SNP allele-specific primers and a universal primer) can be used for an n-plex PCR amplification; the specificity of PCR is thus enhanced significantly. It is concluded that ALM-ASA can be used for typing multiple SNPs simultaneously.
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PMID:[Adapter-ligation mediated allele-specific amplification (ALM-ASA) for multiplex SNP genotyping]. 1652 Mar 20