摘要:

Drug and alcohol seeking behaviour has become a great global problem affecting millions of inhabitants with a cost to society in the billions. Dopaminergic reward pathways have frequently been implicated in the etiology of addictive behaviour. While other neurotransmitters have also been implicated, to date the only molecular genetic defect which has been found to associate with alcoholism, drug dependency, obesity, smoking, pathological gambling, attention-deficit-hyperactivity disorder (ADHD), Tourette syndrome, as well as other related compulsive behaviours, are the variants of the dopamine D2 receptor gene (DRD2). In this review of the available data on the subject, we report a number of independent meta-analyses that confirm an association of DRD2 polymorphisms and impulsive-addictive-compulsive behaviour (IACB), which we have termed “Reward Deficiency Syndrome”. While we agree that Meta-analyses of all exant studies support an association of variants of DRD2 and IACB, correct negative findings with alcoholism may be due to differences in assessing controls and inclusion/exclusion criteria for selection of diseased probands.

ISSN:0960-314X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Chlorzoxazone, a muscle-relaxing drug, is metabolized by carbon-hydroxylation at position 6. Chlorzoxazone has been suggested as an in vivo probe for CYP2E1. We studied the specificity of such a substrate using vaccinia virus expressed human P450 forms and the effect of inhibitors for chlorzoxazone metabolism by human liver microsomes. The 6- hydroxylation of chlorzoxazone was mediated by CYP1A2 as well as by CYP2E1. The Km value of CYP1A2 and CYP2E1 for the reaction was 5.69 µM and 232 µM, respectively. However, the Vmaxvalue of CYP2E1 for the reaction was approximately 8.5-fold higher than that of CYP1A2. The CYP1A inhibitor, alpha-naphthoflavone, as well as the CYP2E1 inhibitor, diethyldithiocarbamate, decreased chlorzoxazone 6-hydroxylation at a low substrate concentration by human liver microsomes. Our results raise questions about the suitability of chlorzoxazone as an in vivo probe for hepatic CYP2E1 activity. In human liver microsomal samples, the Km=40 µM was different from either the Kmof CYP1A2 or CYP2E1. We think that this discrepancy is due to the co-expression of similar levels of CYP1A2 and CYP2E1 in human liver. Furthermore, it is suggested that the role of CYP2E1 in 6-hydroxychlorzoxazone formation at the physiological chlorzoxazone concentration of 30- 60 µM is almost the same when compared to that of CYP1A2.

ISSN:0960-314X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The Ah receptor (Ahr) is a ligand-dependent transcription factor that positively regulates inducible expression of the CYP1A1 gene. Based on the sequence information of the human Ahr and the intron-exon junctions of the mouse counterpart, an analysis of single-strand conformational polymorphism (SSCP) was carried out to detect subtle base differences in the coding region of the gene among individuals. We found that the Ahr protein has at least two forms of variants in a Japanese gene pool, and that these variants can be ascribed to one amino acid replacement of Arg by Lys at codon 554. The frequencies of Arg-coded and Lyscoded alleles were 0.57 and 0.43, respectively. We found, however, that this germ line polymorphism of the Ahr gene did not show a significant association with aryl hydrocarbon hydroxylase (AHH) inducibility nor with lung cancer incidence.

ISSN:0960-314X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

TheCYP2D6genotype and the debrisoquine and mephenytoin hydroxylation phenotypes were studied in 63 Oriental subjects including 21 Chinese, 21 Japanese and 21 Koreans. All subjects were extensive metabolizers of debrisoquine. The incidence of the S-mephenytoin poor metabolizer phenotype was 14% in the Chinese, 24% in the Japanese and 24% in the Korean population, respectively, which is similar to previous reports. TheCYP2D6genotype was analysed by XbaI and Eco RI RFLP, and by allele-specific PCR analysis for the presence of several allelic variants of theCYP2Dlocus. NoCYP2D6AorCYP2D6Balleles, two of the most common defect alleles among Caucasians, were found among the Oriental subjects. The frequency of the CYP2D6D allele was similar to that in Caucasian populations and consistent with the low incidence of the poor metabolizer phenotype in all three Oriental populations. TheCYP2D6L2-allele with duplication of an activeCYP2D6Lgene was identified in one Korean and one Chinese allele in association with highCYP2D6activity. TheCYP2D6ChallelesCYP2D6Ch2and Ch2, identified by RFLP and PCR for the -1338C &U21E2; T and 188C &U21E2; T mutations, were the most frequent allelic variants in all three populations studied, and were related to a decreasedCYP2D6activity as previously shown in Chinese. In conclusion, the present pilot study revealed major similarities in the polymorphicCYP2Dlocus between Korean, Japanese and Chinese populations.

ISSN:0960-314X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Aminoglycoside induced deafness has been linked recently to a predisposing homoplasmic mutation in the 3' end of the small ribosomal RNA (rRNA) gene of the human mitochondria (1555 A&U21E2; G) that makes the mitochondrial rRNA structurally more similar to its bacterial counterpart. This mitochondrial DNA mutation was consistently found in families in which the susceptibility to develop ototoxic deafness was inherited through the maternal lineage. However, the 1555 A&U21E2; G mutation was rarely found in sporadic patients in China, where a significant proportion of the population has been exposed to aminoglycosides. To further characterize the mutations predisposing to aminoglycoside ototoxicity, we analysed the 12S rRNA gene in 3 5 Chinese sporadic patients without the 1555 A&U21E2; G mutation. Using single stranded conformational polymorphism (SSCP) analysis, heteroduplex (HD) analysis, sequencing, and allele specific oligonucleotide hybridization, we found three out of 35 sporadic patients with unique sequence changes in the 12S rRNA gene. Two of the patients had homoplasmic mutations. One patient displayed localized heteroplasmy around nt 961, with an absence of the thymidine at this position and different populations of mitochondrial DNA with varying numbers of inserted cytosines. The description of these putative susceptibility mutations, in particular the heteroplasmic mutation around nt 961, provides further support for the important role of the mitochondrial 12S rRNA in genetic predisposition to aminoglycoside induced ototoxic deafness.

ISSN:0960-314X    

出版商:OVID    

年代:1995

数据来源: OVID

ISSN:0960-314X    

出版商:OVID    

年代:1995

数据来源: OVID

ISSN:0960-314X    

出版商:OVID    

年代:1995

数据来源: OVID

ISSN:0960-314X    

出版商:OVID    

年代:1995

数据来源: OVID